bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2023‒08‒27
fifty papers selected by
Peio Azcoaga, Biodonostia HRI

  1. Cytokine Growth Factor Rev. 2023 Aug 12. pii: S1359-6101(23)00048-5. [Epub ahead of print]
      Myeloid-derived suppressor cells (MDSCs) are important components of the tumor microenvironment (TME), which drive the tumor immune escape by inducing immunosuppression. The expansion and function of MDSCs are tightly associated with signaling pathways induced by molecules from tumor cells, stromal cells, and activated immune cells in the TME. Although these pathways have been well-characterized, the understanding of the epigenetic regulators involved is incomplete. Since histone modifications are the most studied epigenetic changes in MDSCs, we summarize current knowledge on the role of histone modifications in MDSCs within this review. We first discuss the influence of the TME on histone modifications in MDSCs, with an emphasis on histone modifications and modifiers that direct MDSC differentiation and function. Furthermore, we highlight current epigenetic interventions that can reverse MDSC-induced immunosuppression by modulating histone modifications and discuss future research directions to fully appreciate the role of histone modifications in MDSCs.
    Keywords:  Epigenetic therapy; Histone modifications; Myeloid-derived suppressor cells; Tumor microenvironment
  2. Cancer Immunol Res. 2023 Aug 21. pii: CIR-23-0045. [Epub ahead of print]
      Long non-coding RNAs (lncRNA) play an important role in gene regulation in both normal tissues and cancer. Targeting lncRNAs is a promising therapeutic approach that has become feasible through the development of gapmer antisense oligonucleotides (ASOs). Metastasis-associated lung adenocarcinoma transcript (Malat1) is an abundant lncRNA whose expression is upregulated in several cancers. While Malat1 increases the migratory and invasive properties of tumor cells, its role in the tumor microenvironment (TME) is still not well defined. We explored the connection between Malat1 and the tumor immune microenvironment (TIME) using several immune competent preclinical syngeneic Tp53-null triple-negative breast cancer (TNBC) mouse models that mimic the heterogeneity and immunosuppressive TME found in human breast cancer. Using a Malat1 ASO we were able to knockdown Malat1 RNA expression resulting in a delay in primary tumor growth, decreased proliferation and increased apoptosis. Additionally, immunophenotyping of tumor-infiltrating lymphocytes (TILs) revealed that Malat1 inhibition altered the TIME, with a decrease in immunosuppressive tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) as well as an increase in cytotoxic CD8+ T cells. Malat1 depletion in tumor cells, TAMs, and MDSCs decreased immunosuppressive cytokine/chemokine secretion while Malat1 inhibition in T cells increased inflammatory secretions and T-cell proliferation. Combination of a Malat1 ASO with chemotherapy or immune checkpoint blockade (ICB) improved the treatment responses in a preclinical model. These studies highlight the immunostimulatory effects of Malat1 inhibition in TNBC, the benefit of a Malat1 ASO therapeutic, and its potential use in combination with chemotherapies and immunotherapies.
  3. Front Pharmacol. 2023 ;14 1256643
    Keywords:  CAF-targeted therapy; cancer; cancer-associated fibroblasts (CAFs); immune cells; tumor microenvironment (TME)
  4. Cell Death Dis. 2023 08 22. 14(8): 541
      Cancer-associated fibroblasts (CAFs) are an important component of the tumor microenvironment that are involved in multiple aspects of cancer progression and considered contributors to tumor immune escape. CAFs exhibit a unique radiation resistance phenotype, and can survive clinical radiation doses; however, ionizing radiation can induce changes in their secretions and influence tumor progression by acting on tumor and immune cells. In this review, we describe current knowledge of the effects of radiation therapies on CAFs, as well as summarizing understanding of crosstalk among CAFs, tumor cells, and immune cells. We highlight the important role of CAFs in radiotherapy resistance, and discuss current and future radiotherapy strategies for targeting CAFs.
  5. Crit Rev Oncol Hematol. 2023 Aug 18. pii: S1040-8428(23)00190-7. [Epub ahead of print]190 104102
      Breast cancer has surpassed lung cancer as the number one cancer worldwide, and invasion and metastasis are still the main causes of death in breast cancer patients. The tumor microenvironment (TME) is an important site for the growth of tumor cells nourished by vascular networks, and various components of the TME interact strongly with cancer cells and are one of the important mechanisms of tumor progression and metastasis. In recent years, many studies have reported that long non-coding RNAs (LncRNAs) are involved in the formation of TME and influence the process of tumorigenesis and metastasis. This paper reviews the basic characteristics and functional roles of LncRNA in breast cancer TME and introduces the various mechanisms of LncRNA in breast cancer microenvironment that induce breast cancer development and metastasis in three directions: immune cells, non-immune cells, and extracellular matrix in TME, providing potential biomarkers or therapeutic targets for clinical practice.
    Keywords:  Breast cancer; Immunocytes; LncRNAs; Non-immune cells; Tumour microenvironment
  6. Mol Ther. 2023 Aug 21. pii: S1525-0016(23)00438-0. [Epub ahead of print]
  7. Trends Cancer. 2023 Aug 17. pii: S2405-8033(23)00142-5. [Epub ahead of print]
      Immunosuppressive regulatory T cells (Tregs) provide a main mechanism of tumor immune evasion. Targeting Tregs, especially in the tumor microenvironment (TME), continues to be investigated to improve cancer immunotherapy. Recent studies have unveiled intratumoral Treg heterogeneity and plasticity, furthering the complexity of the role of Tregs in tumor immunity and immunotherapy response. The phenotypic and functional diversity of intratumoral Tregs can impact their response to therapy and may offer new targets to modulate specific Treg subsets. In this review we provide a unifying framework of critical factors contributing to Treg heterogeneity and plasticity in the TME, and we discuss how this information can guide the development of more specific Treg-targeting therapies for cancer immunotherapy.
    Keywords:  cancer immunotherapy; immunotolerance; lineage instability; regulatory T cells; tumor microenvironment
  8. Cytokine. 2023 Aug 18. pii: S1043-4666(23)00212-0. [Epub ahead of print]170 156334
      The tumor microenvironment (TME) is a heterogeneous mixture of resident and tumor cells that maintain close communication through their secretion products. The composition of the TME is dynamic and complex among the different types of cancer, where the immune cells play a relevant role in the elimination of tumor cells, however, under certain circumstances they contribute to tumor development. In cervical cancer (CC) the human papilloma virus (HPV) shapes the microenvironment in order to mediate persistent infections that favors transformation and tumor development. Interleukin-2 (IL-2) is an important TME cytokine that induces CD8+ effector T cells and NKs to eliminate tumor cells, however, IL-2 can also suppress the immune response through Treg cells. Recent studies have shown that CC cells express the IL-2 receptor (IL-2R), that are induced to proliferate at low concentrations of exogenous IL-2 through alterations in the JAK/STAT pathway. This review provides an overview of the main immune cells that make up the TME in CC, as well as the participation of IL-2 in the tumor promotion. Finally, it is proposed that the low density of IL-2 produced by immunocompetent cells is used by tumor cells through its IL-2R as a mechanism to proliferate simultaneously depleting this molecule in order to evade immune response.
    Keywords:  Cervical cancer; HPV E6 and E7; IL-2; IL-2R; Tumor microenvironment
  9. Oncoscience. 2023 ;10 34-35
    Keywords:  deposition; embolization; lipiodol; liver tumor; washout
  10. Int J Mol Sci. 2023 Aug 16. pii: 12837. [Epub ahead of print]24(16):
      The microenvironment of most tumors is complex, comprising numerous aspects of immunosuppression. Several studies have indicated that the adrenergic system is vital for controlling immunological responses. In the context of the tumor microenvironment, nor-adrenaline (NA) is poured in by innervating nerves and tumor tissues itself. The receptors for nor-adrenaline are present on the surfaces of cancer and immune cells and are often involved in the activation of pro-tumoral signaling pathways. Beta2-adrenergic receptors (β2-ARs) are an emerging class of receptors that are capable of modulating the functioning of immune cells. β2-AR is reported to activate regulatory immune cells and inhibit effector immune cells. Blocking β2-AR increases activation, proliferation, and cytokine release of T lymphocytes. Moreover, β2-AR deficiency during metabolic reprogramming of T cells increases mitochondrial membrane potential and biogenesis. In the view of the available research data, the immunosuppressive role of β2-AR in T cells presents it as a targetable checkpoint in CAR-T cell therapies. In this review, we have abridged the contemporary knowledge about adrenergic-stress-mediated β2-AR activation on T lymphocytes inside tumor milieu.
    Keywords:  CAR-T therapy; immunosuppression; immunotherapy; tumor microenvironment; β2-adrenergic receptor
  11. Int Rev Immunol. 2023 Aug 21. 1-9
      Innate lymphoid cells are a mixed population of cells and critical regulators of our innate immune system. According to recent scientific literature, tissue resident innate lymphoid cell subtype 2 has been recognized as an important player of type 2 inflammatory responses, involved in different human malignancies like pancreatic, lung, acute myeloid leukemia, gastrointestinal tract cancer, etc. The current reports have revealed that, among the three main ILC sub types, subtype 2 (ILC 2), as the key regulator of initiating the type 2 inflammatory responses at the tumor microenvironment (TME). This activation of ILC-2 is a very important step for the specific downstream functioning of ILC-2. Priming of ILC-2 with different chemokines involves different cytokine secretion from the activated ILC-2 like IL-4, IL-5, IL-13, IL-9 which induce type 2 inflammatory responses involved in the complex interaction with other immune cells like NK cell, Cytotoxic T cell, MDSC and Treg cell. At the initial stage, ILC-2 activation through IL-33 may induce the anti-tumorigenic effect mediated by ILC-2/eosinophil axis. However, it is also evident that PDG2 (Prostaglandin D2)-mediated activation of ILC-2 induces the ILC-2/MDSC immune suppressive pro-tumorigenic niche at the TME. Here, in this review, we have summarized the function of ILC-2 on cancer immunity based on recent scientific work which indicates ILC-2 plays a dual role and orchestrates the immune responses toward type 2 immunity in different cancer settings.
    Keywords:  Cytokine; ILC; immunoregulation; inflammation
  12. Sci Adv. 2023 Aug 25. 9(34): eadd7399
      Regulatory T (Treg) cells and cancer-associated fibroblasts (CAFs) jointly promote tumor immune tolerance and tumorigenesis. The molecular apparatus that drives Treg cell and CAF coordination in the tumor microenvironment (TME) remains elusive. Interleukin 33 (IL-33) has been shown to enhance fibrosis and IL1RL1+ Treg cell accumulation during tumorigenesis and tissue repair. We demonstrated that IL1RL1 signaling in Treg cells greatly dampened the antitumor activity of both IL-33 and PD-1 blockade. Whole tumor single-cell RNA sequencing (scRNA-seq) analysis and blockade experiments revealed that the amphiregulin (AREG)-epidermal growth factor receptor (EGFR) axis mediated cross-talk between IL1RL1+ Treg cells and CAFs. We further demonstrated that the AREG/EGFR axis enables Treg cells to promote a profibrotic and immunosuppressive functional state of CAFs. Moreover, AREG mAbs and IL-33 concertedly inhibited tumor growth. Our study reveals a previously unidentified AREG/EGFR-mediated Treg/CAF coupling that controls the bifurcation of fibroblast functional states and is a critical barrier for cancer immunotherapy.
  13. J Biomed Sci. 2023 Aug 21. 30(1): 69
      Extracellular communication, in other words, crosstalk between cells, has a pivotal role in the survival of an organism. This communication occurs by different methods, one of which is extracellular vesicles. Exosomes, which are small lipid extracellular vesicles, have recently been discovered to have a role in signal transduction between cells inside the body. These vesicles contain important bioactive molecules including lipids, proteins, DNA, mRNA, and noncoding RNAs such as microRNAs (miRNAs). Exosomes are secreted by all cells including immune cells (macrophages, lymphocytes, granulocytes, dendritic cells, mast cells) and tumor cells. The tumor microenvironment (TME) represents a complex network that supports the growth of tumor cells. This microenvironment encompasses tumor cells themselves, the extracellular matrix, fibroblasts, endothelial cells, blood vessels, immune cells, and non-cellular components such as exosomes and cytokines. This review aims to provide insights into the latest discoveries concerning how the immune system communicates internally and with other cell types, with a specific focus on research involving exosomal miRNAs in macrophages, dendritic cells, B lymphocytes, and T lymphocytes. Additionally, we will explore the role of exosomal miRNA in the TME and the immunomodulatory effect.
    Keywords:  Biogenesis; Cancer; Exosomes; Immune cells; Tumor microenvironment; miRNA
  14. Cancers (Basel). 2023 Aug 08. pii: 4014. [Epub ahead of print]15(16):
      Cancer immunotherapies, while promising and occasionally even curative, encounter numerous hurdles within the tumor microenvironment that hinder their efficacy [...].
  15. Front Oncol. 2023 ;13 1236246
      The epidermal growth factor receptor (EGFR) is the most frequently altered gene in glioblastoma (GBM), which plays an important role in tumor development and anti-tumor immune response. While current molecular targeted therapies against the EGFR signaling pathway and its downstream key molecules have not demonstrated favorable clinical outcomes in GBM. Whereas tumor immunotherapies, especially immune checkpoint inhibitors, have shown durable antitumor responses in many cancers. However, the clinical efficacy is limited in patients carrying EGFR alterations, indicating that EGFR signaling may involve tumor immune response. Recent studies reveal that EGFR alterations not only promote GBM cell proliferation but also influence immune components in the tumor microenvironment (TME), leading to the recruitment of immunosuppressive cells (e.g., M2-like TAMs, MDSCs, and Tregs), and inhibition of T and NK cell activation. Moreover, EGFR alterations upregulate the expression of immunosuppressive molecules or cytokines (such as PD-L1, CD73, TGF-β). This review explores the role of EGFR alterations in establishing an immunosuppressive TME and hopes to provide a theoretical basis for combining targeted EGFR inhibitors with immunotherapy for GBM.
    Keywords:  epidermal growth factor receptor; glioblastoma; immune cell; immunosuppression; tumor microenvironment
  16. bioRxiv. 2023 Aug 13. pii: 2023.08.09.552650. [Epub ahead of print]
      An effective cancer therapy requires both killing cancer cells and targeting tumor-promoting pathways or cell populations within the tumor microenvironment (TME). We purposely search for molecules that are critical for multiple tumor-promoting cell types and identified nuclear receptor subfamily 4 group A member 1 (NR4A1) as one such molecule. NR4A1 has been shown to promote the aggressiveness of cancer cells and maintain the immune suppressive TME. Using genetic and pharmacological approaches, we establish NR4A1 as a valid therapeutic target for cancer therapy. Importantly, we have developed the first-of-its kind proteolysis-targeting chimera (PROTAC, named NR-V04) against NR4A1. NR-V04 effectively degrades NR4A1 within hours of treatment in vitro and sustains for at least 4 days in vivo , exhibiting long-lasting NR4A1-degradation in tumors and an excellent safety profile. NR-V04 leads to robust tumor inhibition and sometimes eradication of established melanoma tumors. At the mechanistic level, we have identified an unexpected novel mechanism via significant induction of tumor-infiltrating (TI) B cells as well as an inhibition of monocytic myeloid derived suppressor cells (m-MDSC), two clinically relevant immune cell populations in human melanomas. Overall, NR-V04-mediated NR4A1 degradation holds promise for enhancing anti- cancer immune responses and offers a new avenue for treating various types of cancer.
  17. Front Oncol. 2023 ;13 1264740
    Keywords:  IMiDs; bone marrow; metabolism; microenvironment; mitochondria; multiple myeloma; proteasome inhibitors (PI)
  18. J Cancer Res Clin Oncol. 2023 Aug 23.
      BACKGROUND: Chimeric antigen receptor (CAR) T cell therapy has shown promising results in treating blood cancers, but it has limited efficacy against solid tumors that express mesothelin (MSLN). One of the reasons is the immunosuppressive tumor microenvironment, which consists of physical barriers, multiple mechanisms of immune evasion, and various biochemical factors that favor tumor growth and survival. These factors reduce the antitumor activity of MSLN-targeted CAR T cells in clinical trials. Therefore, new therapeutic strategies are needed to enhance the effectiveness of MSLN-targeted CAR T cell therapy.METHODS: To investigate whether the antitumor efficacy of anti-MSLN CAR-T cells depends on the epitopes they recognize, we generated MSLN-targeted CAR T cells that bind to different regions of MSLN (Region I, II, III and Full length). We then evaluated the antitumor activity of MSLN-targeted CAR T cells alone or in combination with the chemotherapeutic drug irinotecan or an anti-PD-1 antibody in vitro and in vivo.
    RESULTS: We found that MSLN-targeted CAR T cells effectively killed MSLN-positive cancer cells (H9, H226 and Panc-1), but not MSLN-negative cells (A431) in vitro. In a mouse model of H9 tumor xenografts, all CAR T cells showed similar tumor suppression, but an MSLN-targeted scFv with Region I epitope, R47, performed slightly better. Combining irinotecan with CAR_R47 T cells enhanced tumor control synergistically in both H9 xenograft mice and patient-derived xenograft mice.
    CONCLUSIONS: Our results suggest that irinotecan can enhance the antitumor activity of MSLN-targeted CAR T cells, and offer a promising combination therapy strategy for MSLN-positive solid tumors.
    Keywords:  Chimeric antigen receptor; Combination therapy; Irinotecan; Mesothelin; Solid cancer
  19. Immunol Invest. 2023 Aug 24. 1-23
      Mesenchymal stem cells (MSCs) are a heterogeneous group of progenitor cells that play a multifunctional role including tissue regeneration, self-renewal properties, and differentiate into cells of mesodermal lineage such as adipocytes, osteoblasts, and chondrocytes. MSCs come into contact with tumor microenvironment (TME) and differentiate into tumor-associated MSCs (TA-MSCs). Various substances such as chemokines, cytokines, growth factors, and others are released by tumor cells to recruit MSCs. TA-MSCs induced epithelial-mesenchymal transition (EMT) program which mediates tumor growth progression, migration, and invasion. Role of MSCs in the tumor progression, stemness, malignancy, and treatment resistance in the breast cancer TME. Immunomodulation by MSCs is mediated by a combination of cell contact-dependent mechanisms and soluble substances. Monocytes/macrophages, dendritic cells, T cells, B cells, and NK cells all show signs of MSCs' immunomodulatory capability. In a complicated interplay initiated by MSCs, anti-inflammatory monocytes/macrophages and regulatory T cells (Tregs) play a key role, as they unveil their full immunomodulatory potential. MSC- secreted cytokines are commonly blamed for the interaction between MSCs, monocytes, and Tregs. Here, we review the current knowledge of cellular and molecular mechanisms involved in MSC-mediated immunomodulation and focus on the role MSCs play in breast cancer progression and its TME.Abbreviation MSC: Mesenchymal Stem Cells; TME: Tumor Microenvironment; TAMS; Tumour-associated Macrophages; ECM: Extracellular matrix; CAFs: Cancer-associated Fibroblasts; CFUs: Colony-forming unit Fibroblasts; Tregs: T regulatory cells; Bregs; Regulatory B cells; IFN-γ: Interferon-gamma; TNF-α: Tumour Necrosis Factor-alpha; IL: Interleukin; TGF-β: transforming growth factorβ; PGE2: Prostaglandin E2; CXCR: Chemokine Receptor; Blimp-1; B lymphocyte-induced maturation protein-1; CCL: Chemokine motif ligand; EMT: Epithelial-mesenchymal transition.
    Keywords:  Breast cancer; immune cells; mesenchymal stem cells; tumor microenvironment
  20. Eur J Pharmacol. 2023 Aug 22. pii: S0014-2999(23)00503-4. [Epub ahead of print] 175991
      The use of repurposing drugs that may have neoplastic and anticancer effects increases the efficiency and decrease resistance to chemotherapy drugs through a biochemical and mechanical transduction mechanisms through modulation of fibroblast/fibrosis remodeling in tumor microenvironment (TME). Interestingly, fibroblast/fibrosis remodeling plays a vital role in mediating cancer metastasis and drug resistance after immune chemotherapy. The most essential hypothesis for induction of chemo-immunotherapy resistance is via activation of fibroblast/fibrosis remodeling and preventing the infiltration of T cells after is mainly due to the interference between cytoskeleton, mechanical, biochemical, metabolic, vascular, and remodeling signaling pathways in TME. The structural components of the tumor that can be targeted in the fibroblast/fibrosis remodeling include the depletion of the TME components, targeting the cancer-associated fibroblasts and tumor associated macrophages, alleviating the mechanical stress within the ECM, and normalizing the blood vessels. It has also been found that during immune-chemotherapy, TME injury and fibroblast/fibrosis remodeling causes the up-regulation of inhibitory signals and down-regulation of activated signals, which results in immune escape or chemo-resistance of the tumor. In this regard, repurposing or neo-adjuvant drugs with various transduction signaling mechanisms, including anti-fibrotic effects, are used to target the TME and fibroblast/fibrosis signaling pathway such as angiotensin 2, transforming growth factor-beta, physical barriers of the TME, cytokines and metabolic factors which finally led to the reverse of the chemo-resistance. Consistent to many repurposing drugs such as pirfenidone, metformin, losartan, tranilast, dexamethasone and pentoxifylline are used to decrease immune-suppression by abrogation of TME inhibitory signal that stimulates the immune system and increases efficiency and reduces resistance to chemotherapy drugs. To overcome immunosuppression based on fibroblast/fibrosis remodeling, in this review, we focus on inhibitory signal transduction, which is the physical barrier, alleviates mechanical stress and prevents mechano-metabolic activation.
    Keywords:  Chemoresistance; Desmoplasia; ECM; Fibroblast/fibrosis remodeling; Mechanotransduction; Metabolic normalization; Metastasis; Reperfusion drug
  21. Pharmaceutics. 2023 Aug 01. pii: 2070. [Epub ahead of print]15(8):
      Exosomes are nanoscale vesicles released by diverse types of cells for complex intercellular communication. Numerous studies have shown that exosomes can regulate the body's immune response to tumor cells and interfere with the tumor microenvironment (TME). In clinical trials on dendritic cell (DC)-based antitumor vaccines, no satisfactory results have been achieved. However, recent studies suggested that DC-derived exosomes (DEXs) may be superior to DC-based antitumor vaccines in avoiding tumor cell-mediated immunosuppression. DEXs contain multiple DC-derived surface markers that capture tumor-associated antigens (TAAs) and promote immune cell-dependent tumor rejection. These findings indicate the necessity of the further development and improvement of DEX-based cell-free vaccines to complement chemotherapy, radiotherapy, and other immunotherapies. In this review, we highlighted the recent progress of DEXs in cancer immunotherapy, particularly by concentrating on landmark studies and the biological characterization of DEXs, and we summarized their important role in the tumor immune microenvironment (TIME) and clinical application in targeted cancer immunotherapy. This review could enhance comprehension of advances in cancer immunotherapy and contribute to the elucidation of how DEXs regulate the TIME, thereby providing a reference for utilizing DEX-based vaccines in clinical practice.
    Keywords:  cancer; dendritic cells; exosomes; immunotherapy
  22. Front Immunol. 2023 ;14 1265434
    Keywords:  bone metastasis; immune checkpoint inhibitor; osteoimmunology; osteosarcoma; tumor microenvironment (TME)
  23. Cancers (Basel). 2023 Aug 21. pii: 4188. [Epub ahead of print]15(16):
      The tumor and tumor microenvironment (TME) consist of a complex network of cells, including malignant, immune, fibroblast, and vascular cells, which communicate with each other. Disruptions in cell-cell communication within the TME, caused by a multitude of extrinsic and intrinsic factors, can contribute to tumorigenesis, hinder the host immune system, and enable tumor evasion. Understanding and addressing intercellular miscommunications in the TME are vital for combating these processes. The effectiveness of immunotherapy and the heterogeneous response observed among patients can be attributed to the intricate cellular communication between immune cells and cancer cells. To unravel these interactions, various experimental, statistical, and computational techniques have been developed. These include ligand-receptor analysis, intercellular proximity labeling approaches, and imaging-based methods, which provide insights into the distorted cell-cell interactions within the TME. By characterizing these interactions, we can enhance the design of cancer immunotherapy strategies. In this review, we present recent advancements in the field of mapping intercellular communication, with a particular focus on immune-tumor cellular interactions. By modeling these interactions, we can identify critical factors and develop strategies to improve immunotherapy response and overcome treatment resistance.
    Keywords:  bioinformatics; cancer; cell–cell interaction; immunotherapy; intercellular imaging; intercellular labeling
  24. Front Mol Biosci. 2023 ;10 1220193
      The tumor microenvironment (TME) is an intricate ecosystem that is actively involved in various stages of cancer occurrence and development. Some characteristics of tumor biological behavior, such as proliferation, migration, invasion, inhibition of apoptosis, immune escape, angiogenesis, and metabolic reprogramming, are affected by TME. Studies have shown that non-coding RNAs, especially long-chain non-coding RNAs and microRNAs in cancer-derived exosomes, facilitate intercellular communication as a mechanism for regulating angiogenesis. They stimulate tumor growth, as well as angiogenesis, metastasis, and reprogramming of the TME. Exploring the relationship between exogenous non-coding RNAs and tumor-associated endothelial cells, as well as their role in angiogenesis, clinicians will gain new insights into treatment as a result.
    Keywords:  cancer; endothelial cells; exosomes; exosomes-derived non-coding RNAs; lncRNA; miRNA; tumor microenvironment; tumorassociated angiogenesis
  25. Clin Exp Med. 2023 Aug 23.
      Chemokines were originally defined as cytokines that affect the movement of immune cells. In recent years, due to the increasing importance of immune cells in the tumor microenvironment (TME), the role of chemokines has changed from a single "chemotactic agent" to a key factor that can regulate TME and affect the tumor phenotype. CXCL6, also known as granulocyte chemoattractant protein-2 (GCP-2), can recruit neutrophils to complete non-specific immunity in the process of inflammation. Cancer-related genes and interleukin family can promote the abnormal secretion of CXCL6, which promotes tumor growth, metastasis, epithelial mesenchymal transformation (EMT) and angiogenesis in the TME. CXCL6 also has a role in promoting fibrosis and tissue damage repair. In this review, we focus on the regulatory network affecting CXCL6 expression, its role in the progress of inflammation and how it affects tumorigenesis and progression based on the TME, in an attempt to provide a potential target for the treatment of diseases such as inflammation and cancer.
    Keywords:  CXCL6; Cancer; Chemokines; GCP-2; Inflammation
  26. Adv Biol (Weinh). 2023 Aug 24. e2300168
      Hyaluronan (HA) is one of the major components of the extracellular matrix in tumor tissue. Recent reports have made it clear that the balance of HA synthesis and degradation is critical for tumor progression. HA is synthesized on the cytoplasmic surface of the plasma membrane by hyaluronan synthases (HAS) and extruded into the extracellular space. Excessive HA production in cancer is associated with enhanced HA degradation in the tumor microenvironment, leading to the accumulation of HA fragments with small molecular weight. These perturbations in both HA synthesis and degradation may play important roles in tumor progression. Recently, it has become increasingly clear that small HA fragments can induce a variety of biological events, such as angiogenesis, cancer-promoting inflammation, and tumor-associated immune suppression. Progression of urologic malignancies, particularly of prostate and bladder cancers, as well as of certain types of kidney cancer show markedly perturbed metabolism of tumor-associated HA. This review highlights the recent research findings regarding HA metabolism in tumor microenvironments with a special focus on urologic cancers. It also will discuss the potential implications of these findings for the development of novel therapeutic interventions for the treatment of prostate, bladder, and kidney cancers.
    Keywords:  bladder cancer; hyaluronan metabolism; kidney cancer; prostate cancer; tumor-associated hyaluronan
  27. Biology (Basel). 2023 Jul 25. pii: 1044. [Epub ahead of print]12(8):
      Pancreatic cancer is one of the deadliest forms of cancer with one of the lowest 5-year survival rates of all cancer types. A defining characteristic of pancreatic cancer is the existence of dense desmoplastic stroma that, when exposed to stimuli such as cytokines, growth factors, and chemokines, generate a tumor-promoting environment. Cancer-associated fibroblasts (CAFs) are activated during the progression of pancreatic cancer and are a crucial component of the tumor microenvironment (TME). CAFs are primarily pro-tumorigenic in their activated state and function as promoters of cancer invasion, proliferation, metastasis, and immune modulation. Aided by many signaling pathways, cytokines, and chemokines in the tumor microenvironment, CAFs can originate from many cell types including resident fibroblasts, mesenchymal stem cells, pancreatic stellate cells, adipocytes, epithelial cells, endothelial cells, and other cell types. CAFs are a highly heterogeneous cell type expressing a variety of surface markers and performing a wide range of tumor promoting and inhibiting functions. Single-cell transcriptomic analyses have revealed a high degree of specialization among CAFs. Some examples of CAF subpopulations include myofibrotic CAFs (myCAFs), which exhibit a matrix-producing contractile phenotype; inflammatory CAFs (iCAF) that are classified by their immunomodulating, secretory phenotype; and antigen-presenting CAFs (apCAFs), which have antigen-presenting capabilities and express Major Histocompatibility Complex II (MHC II). Over the last several years, various attempts have been undertaken to describe the mechanisms of CAF-tumor cell interaction, as well as CAF-immune cell interaction, that contribute to tumor proliferation, invasion, and metastasis. Although our understanding of CAF biology in cancer has steadily increased, the extent of CAFs heterogeneity and their role in the pathobiology of pancreatic cancer remains elusive. In this regard, it becomes increasingly evident that further research on CAFs in pancreatic cancer is necessary.
    Keywords:  cancer-associated fibroblasts (CAFs); extracellular matrix (ECM); heterogeneity; metastasis; pancreatic ductal adenocarcinoma (PDAC); proliferation; tumor microenvironment (TME)
  28. Curr Opin Cell Biol. 2023 Aug 17. pii: S0955-0674(23)00067-4. [Epub ahead of print]84 102218
      Cell function relies on the spatiotemporal dynamics of metabolic reactions. In all physiopathological processes of tissues, mechanical forces impact the structure and function of membranes, enzymes, organelles and regulators of metabolic gene programs, thus regulating cell metabolism. In turn, metabolic pathways feedback impacts the physical properties of cell and tissues. Hence, metabolism and tissue mechanics are dynamically intertwined and continuously interact. Cancer is akin to an ecosystem, comprising tumor cells and various subpopulations of stromal cells embedded in an altered extracellular matrix. The progression of cancer, from initiation to advanced stage and metastasis, is driven by genetic mutations and crucially influenced by physical and metabolic alterations in the tumor microenvironment. These alterations also play a pivotal role in cancer cells evasion from immune surveillance and in developing resistance to treatments. Here, we highlight emerging evidence showing that mechano-metabolic circuits in cancer and stromal cells regulate multiple processes crucial for tumor progression and discuss potential approaches to improve therapeutic treatments by interfering with these circuits.
  29. Cells. 2023 Aug 10. pii: 2036. [Epub ahead of print]12(16):
      Hepatocellular carcinoma (HCC) is a primary liver cancer with a high mortality rate and limited treatment options. Recent research has brought attention to the significant importance of intercellular communication in the progression of HCC, wherein exosomes have been identified as critical agents facilitating cell-to-cell signaling. In this article, we investigate the impact of macrophages as both sources and targets of exosomes in HCC, shedding light on the intricate interplay between exosome-mediated communication and macrophage involvement in HCC pathogenesis. It investigates how exosomes derived from HCC cells and other cell types within the tumor microenvironment (TME) can influence macrophage behavior, polarization, and recruitment. Furthermore, the section explores the reciprocal interactions between macrophage-derived exosomes and HCC cells, stromal cells, and other immune cells, elucidating their role in tumor growth, angiogenesis, metastasis, and immune evasion. The findings presented here contribute to a better understanding of the role of macrophage-derived exosomes in HCC progression and offer new avenues for targeted interventions and improved patient outcomes.
    Keywords:  exosomes; extracellular vesicles; hepatocellular carcinoma (HCC); immunotherapy; macrophages; tumor microenvironment (TME)
  30. Biomater Sci. 2023 Aug 23.
      Cancer vaccine-based immunotherapy has great potential; however, the vaccines have been hindered by the immunosuppressive tumor microenvironment (TME). In this study, dual-responsive PEG-lipid polyester nanoparticles (PEG BR647-NPs) for tumor-targeted delivery were proposed. PEG BR647-NPs containing the model tumor-associated antigen (TAA) OVA and the signal transduction and activator of transcription 3 (STAT3) siRNA were delivered to the tumor. The PEG BR647-NPs were internalized by tumor-associated dendritic cells (TADCs), where the TAA and siRNA were released into the cytoplasm via the endo/lysosome escape effect. The released OVA was presented by the major histocompatibility complex class I to activate T cells, and the released STAT3 siRNA acted to relieve TADC dysfunction, promote TADC maturation, improve antigen-presenting ability, and enhance anticancer T cell immunity. Meanwhile, the PEG BR647-NPs were ingested by tumor cells, killing them by the pro-apoptosis effect of STAT3 siRNA. Moreover, PEG BR647-NPs could reduce the proportion of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) in tumors and abrogate immunosuppression. The integration of relieved TADC dysfunction, promoted TADC maturation, enhanced antigen cross-presentation, abrogated immunosuppression, and improved pro-apoptosis effect boosted the vaccination for tumor immunotherapy. Thus, PEG BR647-NPs efficiently delivered the vaccine and STAT3 siRNA to the tumor and modulated immunosuppressive TME, thus providing better antitumor effects.
  31. Int J Mol Sci. 2023 Aug 16. pii: 12836. [Epub ahead of print]24(16):
      There is a growing body of evidence supporting the significant role of bacterial biofilms in the pathogenesis of various human diseases, including cancer. Biofilms are polymicrobial communities enclosed within an extracellular matrix composed of polysaccharides, proteins, extracellular DNA, and lipids. This complex matrix provides protection against antibiotics and host immune responses, enabling the microorganisms to establish persistent infections. Moreover, biofilms induce anti-inflammatory responses and metabolic changes in the host, further facilitating their survival. Many of these changes are comparable to those observed in cancer cells. This review will cover recent research on the role of bacterial biofilms in carcinogenesis, especially in colorectal (CRC) and gastric cancers, emphasizing the shared physical and chemical characteristics of biofilms and cancer. This review will also discuss the interactions between bacteria and the tumor microenvironment, which can facilitate oncogene expression and cancer progression. This information will provide insight into developing new therapies to identify and treat biofilm-associated cancers, such as utilizing bacteria as delivery vectors, using bacteria to upregulate immune function, or more selectively targeting biofilms and cancer for their shared traits.
    Keywords:  Fusobacterium nucleatum (Fn); Helicobacter pylori (Hp); colorectal cancer (CRC); extracellular polymeric substance (EPS); tumor microbiome (TM); tumor microenvironment (TME); tumor-associated macrophages (TAM)
  32. Transl Gastroenterol Hepatol. 2023 ;8 29
      The liver is a functionally unique organ with an immunosuppressive microenvironment. The liver is the sixth most common site of primary cancer in humans and is a frequent site of metastasis from other solid tumors. The development of effective therapies for primary and metastatic liver cancer has been challenging due to the complex metabolic and immune microenvironment of the liver. The liver tumor microenvironment (TME) in primary and secondary (metastatic) liver cancers is heterogenous and consists of unique immune and stromal cell populations. Crosstalk between these cell populations and tumor cells creates an immunosuppressive microenvironment within the liver which potentiates cancer progression. Immune checkpoint inhibitors (ICIs) are now clinically approved for the management of primary and secondary liver cancer and can partially overcome liver immune tolerance, but their efficacy is limited. In this review, we describe the liver microenvironment and the use of immunotherapy in primary and secondary liver cancer. We discuss emerging combination strategies utilizing locoregional and systemic therapy approaches which may enhance efficacy of immunotherapy in primary and secondary liver cancer. A deeper understanding of the immunosuppressive microenvironment of the liver will inform novel therapies and therapeutic combinations in order to improve outcomes of patients with primary and secondary liver cancer.
    Keywords:  Hepatocellular carcinoma (HCC); immunotherapy in liver cancer; liver metastases; tumor immune microenvironment
  33. Platelets. 2023 Dec;34(1): 2247489
      The contribution of platelets is well recognized in thrombosis and hemostasis. However, platelets also promote tumor progression and metastasis through their crosstalk with various cells of the tumor microenvironment (TME). For example, several cancer models continue to show that platelet functions are readily altered by cancer cells upon activation leading to the formation of platelet-tumor aggregates, triggering release of soluble factors from platelet granules and altering platelet turnover. Further, activated platelets protect tumor cells from shear forces in circulation and assault of cytotoxic natural killer (NK) cells. Platelet-secreted factors promote proliferation of malignant cells, metastasis, and chemoresistance. Much of our knowledge of platelet biology in cancer has been achieved with animal models, particularly murine. However, this preclinical understanding of the complex pathophysiology is yet to be fully realized and translated to clinical trials in terms of new approaches to treat cancer via controlling the platelet function. In this review, we summarize the current state of knowledge of platelet physiology obtained through existing in vivo and in vitro cancer models, the complex interactions of platelets with cancer cells in TME and the pathways by which platelets may confer chemoresistance. Since the FDA Modernization Act recently passed by the US government has made animal models optional in drug approvals, we critically examine the existing and futuristic value of employing bioengineered microphysiological systems and organ-chips to understand the mechanistic role of platelets in cancer metastasis and exploring novel therapeutic targets for cancer prevention and treatment.
    Keywords:  Cancer; drug discovery; microphysiological systems; organ-chips; platelets; tumor microenvironment
  34. Int J Cancer. 2023 Aug 21.
      Tumor progression and response to treatment are highly affected by interactions between cancer cells and the tumor microenvironment (TME). Many of the soluble factors and signaling receptors involved in this crosstalk are shed by a disintegrin and metalloproteinases (ADAMs). Upregulation of ADAM15 has been linked to worse survival in cancer patients and a tumor-promoting function both in vitro and in murine cancer models. Although ADAM15 has been involved in cell-cell and cell-extracellular matrix interactions, its role in the crosstalk between cancer cells and the TME in vivo remains unexplored. Therefore, we aimed to understand how ADAM15 regulates the cell composition of the TME and how it affects tumor progression. Here, we showed an upregulation of ADAM15 in tumor tissues from rectal cancer patients. Subcutaneous injection of wildtype and ADAM15-knockout CT26 colon cancer cells in syngeneic mice confirmed the protumorigenic role of ADAM15. Profiling of tumors revealed higher immune cell infiltration and cancer cell apoptosis in the ADAM15-deficient tumors. Specifically, loss of ADAM15 led to a reduced number of granulocytes and higher infiltration of antigen-presenting cells, including dendritic cells and macrophages, as well as more T cells. Using in vitro assays, we confirmed the regulatory effect of ADAM15 on macrophage migration and identified ADAM15-derived CYR61 as a potential molecular mediator of this effect. Based on these findings, we speculate that targeting ADAM15 could increase the infiltration of immune cells in colorectal tumors, which is a prerequisite for effective immunotherapy.
    Keywords:  CCN1; cancer; immunotherapy; macrophages; metargidin
  35. Pharmacol Ther. 2023 Aug 23. pii: S0163-7258(23)00183-3. [Epub ahead of print] 108519
      Lactate acidosis is often observed in the tumor microenvironment (TME) of solid tumors. This is because glucose breaks down quickly via glycolysis, causing lactate acidity. Lactate is harmful to healthy cells, but is a major oncometabolite for solid cancer cells that do not receive sufficient oxygen. As an oncometabolite, it helps tumor cells perform different functions, which helps solid hypoxic tumor cells spread to other parts of the body. Studies have shown that the acidic TME contains VEGF, Matrix metalloproteinases (MMPs), cathepsins, and transforming growth factor-β (TGF-β), all of which help spread in direct and indirect ways. Although each cytokine is important in its own manner in the TME, TGF-β has received much attention for its role in metastatic transformation. Several studies have shown that lactate acidosis can cause TGF-β expression in solid hypoxic cancers. TGF-β has also been reported to increase the production of fatty acids, making cells more resistant to treatment. TGF-β has also been shown to control the expression of VEGF and MMPs, which helps solid hypoxic tumors become more aggressive by helping them spread and create new blood vessels through an unknown process. The role of TGF-β under physiological conditions has been described previously. In this study, we examined the role of TGF-β, which is induced by lactate acidosis, in the spread of solid hypoxic cancer cells. We also found that TGF-β and lactate work together to boost fatty acid production, which helps angiogenesis and invasiveness.
    Keywords:  Angiogenesis; Fatty acid synthesis; Hypoxia; Invasiveness; Transforming growth factor (TGF-β)
  36. Curr Opin Oncol. 2023 Jun 27.
      PURPOSE OF REVIEW: Inflammatory breast cancer (IBC) is the most fatal type presentation of clinical breast cancer. The immune tumor microenvironment (TME) of IBC is characterized by signals of immune evasion but suggests actionable vulnerability to immune-checkpoint inhibitors (ICIs). In this review, we aimed to summarize the most important preclinical evidences of IBC immune-vulnerability and the first data from clinical trials evaluating ICIs in IBC.RECENT FINDINGS: IBC is characterized by a preexisting active immune TME suppressed by mechanisms of immune-escape, including inhibitory immune-checkpoints, whose expression is higher than in non-IBC. Clinical trials evaluating ICIs in patients with IBC are burdened by slow accrual and low enrollment.
    SUMMARY: Because of the limited data from clinical trials, no conclusions about the activity of ICIs in IBC can be drawn. Ongoing clinical trials are assessing many promising ICI-based combination approaches. An enhanced multicenter collaboration to evaluate ICIs in patients with this aggressive form of disease and to improve clinical outcomes is required.
  37. Appl Immunohistochem Mol Morphol. 2023 Aug 25.
      Compelling data has demonstrated the prognostic significance of tumor-infiltrating lymphocytes (TILs) in triple-negative breast cancer (TNBC), a subtype generally associated with a poor clinical outcome but highly heterogeneous in nature. There have been limited studies investigating the importance of subsets of T cells in TILs. Further, the significance of intratumoral versus peritumoral TILs remains controversial. We examined the prognostic value of tumor-associated CD8+ cytotoxic T cells and FOXP3+ regulatory T cells in 35 chemotherapy-naive TNBC cases with a tumor-host interface in the tissue sections. The CD8+ and FOXP3+ cell count was expressed by immunoreactive cells per high-power field in an average of 10 high-power fields. There was a wide range of CD8+ and FOXP3+ T cells within the peritumoral and intratumoral stroma. Both CD8+ and FOXP3+ TILs were significantly higher at the former location as compared with the latter (P<0.0001 and 0.003, respectively). The numbers of CD8+ and FOXP3+ T cells, either within peritumoral or intratumoral stroma, were not significantly associated with distant relapse-free or disease-specific survival. However, the peritumoral CD8+/FOXP3+ ratio of TILs was significantly associated with prolonged relapse-free survival (P=0.04) and disease-specific survival (P=0.02). This association was not observed with the CD8+/FOXP3+ ratio of intratumoral TILs. These observations suggest that the immunologic balance in the tumor microenvironment might determine antitumor immunity. Further, the peritumoral TILs appear to play a more important role in the progression of TNBC when compared with the intratumoral TILs, thus reaffirming the necessity of revisiting the method for the assessment of TILs.
  38. J Cell Sci. 2023 Aug 25. pii: jcs.260964. [Epub ahead of print]
      Triple negative breast cancer (TNBC) is the most aggressive and poorly-treated subtype of breast cancer. Identifying novel drivers and mechanisms for tumor progression is quite essential for precise targeted therapy of TNBC. Immunoglobulin-like transcript (ILT) 4 is a classic myeloid suppressor for their activation and immune response. Our recent results found that ILT4 is also high expressed in lung cancer cells where has a role in promoting immune evasion and thus tumor formation. However, the expression and function of ILT4 in breast cancer remains elusive. Here, using our patient cohort and public database analysis, we found that TNBC displayed the most abundant ILT4 expression among all breast cancer subtypes. Functionally, enriched ILT4 promoted TNBC cell proliferation, migration and invasion in vitro, as well as tumor growth and metastasis in vivo. Further mechanistic analysis revealed that ILT4 reprogrammed aerobic glycolysis of tumor cells via AKT/mTOR signaling-mediated glucose transporter 3 (GLUT3) and Pyruvate kinase muscle 2 (PKM2) overexpression. ILT4 inhibition in TNBC reduced tumor progression and GLUT3/PKM2 expression in vivo. Our study identified a novel driver for TNBC progression and proposed a promising strategy to combat TNBC by targeting ILT4.
    Keywords:  Glucose metabolism; ILT4; Motility; Proliferation; Triple negative breast cancer
  39. J Pers Med. 2023 Aug 14. pii: 1261. [Epub ahead of print]13(8):
      Tumor behavior is determined by its interaction with the tumor microenvironment (TME). Chimeric antigen receptor (CART) cell therapy represents a new form of cellular immunotherapy (IT). Immune cells present a different sensitivity to radiation therapy (RT). RT can affect tumor cells both modifying the TME and inducing DNA damage, with different effects depending on the low and high doses delivered, and can favor the expression of CART cells. CART cells are patients' T cells genetically engineered to recognize surface structure and to eradicate cancer cells. High-dose radiation therapy (HDRT, >10-20 Gy/fractions) converts immunologically "cold" tumors into "hot" ones by inducing necrosis and massive inflammation and death. LDRT (low-dose radiation therapy, >5-10 Gy/fractions) increases the expansion of CART cells and leads to non-immunogenetic death. An innovative approach, defined as the LATTICE technique, combines a high dose in higher FDG- uptake areas and a low dose to the tumor periphery. The association of RT and immune checkpoint inhibitors increases tumor immunogenicity and immune response both in irradiated and non-irradiated sites. The aim of this narrative review is to clarify the knowledge, to date, on CART cell therapy and its possible association with radiation therapy in solid tumors.
    Keywords:  CART; immunotherapy; radiotherapy; solid tumor; tumor microenvironment
  40. Mol Pharm. 2023 Aug 19.
      Cancer remains the leading cause of death and rapidly evolving disease worldwide. The understanding of disease pathophysiology has improved through advanced research investigation, and several therapeutic strategies are being used for better cancer treatment. However, the increase in cancer relapse and metastatic-related deaths indicate that available therapies and clinically approved chemotherapy drugs are not sufficient to combat cancer. Further, the constant crosstalk between tumor cells and the tumor microenvironment (TME) is crucial for the development, progression, metastasis, and therapeutic response to tumors. In this regard, phytochemicals with multimodal targeting abilities can be used as an alternative to current cancer therapy by inhibiting cancer survival pathways or modulating TME. However, due to their poor pharmacokinetics and low bioavailability, the success of phytochemicals in clinical trials is limited. Therefore, developing phytochemical-based nanomedicine or phytonanomedicine can improve the pharmacokinetic profile of these phytochemicals. Herein, the molecular characteristics and pharmacological insights of the proposed phytonanomedicine in cancer therapy targeting tumor tissue and altering the characteristics of cancer stem cells, chemoresistance, TME, and cancer immunity are well discussed. Further, we have highlighted the clinical perspective and challenges of phytonanomedicine in filling the gap in potential cancer therapeutics using various nanoplatforms. Overall, we have discussed how clinical success and pharmacological insights could make it more beneficial to boost the concept of nanomedicine in the academic and pharmaceutical fields to counter cancer metastases and drug resistance.
    Keywords:  cancer stem cells; cancer therapy; nanomedicine; phytochemicals; phytonanomedicine; signaling pathways; tumor microenvironment
  41. Front Pharmacol. 2023 ;14 1159829
      Jianpi Yangzheng Xiaozheng decoction (JPYZXZ) is an empirical traditional Chinese medicine formula that has been reported to significantly prolong the survival of patients with advanced gastric cancer (GC). However, its underlying mechanism have not been fully elucidated. The present work aims to explore the possible mechanism of JPYZXZ on regulating GC progression. We firstly confirmed the inhibitory effect of JPYZXZ in GC MKN74 cells and 615-strain mice, which was possibly mediated with IL-6/JAK2/STAT3 pathway dependent PD-L1 expression. Moreover, we showed that JPYZXZ diminished the expression levels of GC-derived exosomal PD-L1 in MFC murine cells and xenograft GC model, as well as stage IIA-IIIB GC patients. We further found that in different types of tumor-infiltrating immune cells, PD-L1 expression was most positively correlated with myeloid-derived suppressor cells (MDSCs) in GC in the TISIDB database. We isolated exosomes derived from supernatants of MFC cells and co-cultured with bone marrow cells derived from C57BL/6 mice, and further revealed that the expansion of MDSCs was mediated by GC-derived exosomal PD-L1. Meanwhile, our results indicated that JPYZXZ inhibited the delivery of exosomal PD-L1 from GC cells to bone marrow cells, thereby alleviating exosomal PD-L1-induced differentiation and expansion of MDSCs in the tumor microenvironment. This led to a decrease in the levels of several immunosuppressive factors, including iNOS, Arg-1, TGF-β, IL-10, and IL-6, in 615-strain mice. Moreover, clinical data also revealed a significant positive relationship between exosomal PD-L1 and polymorphonuclear MDSCs under the JPYZXZ treatment in stage IIA-IIIB GC patients. In conclusion, our study confirmed that exosomal PD-L1 could be a key factor in controlling MDSCs differentiation in GC. JPYZXZ alleviated GC progression via suppressing exosomal PD-L1 mediated expansion of MDSCs, thereby remodeling the immunosuppressive tumor microenvironment, which provided the experimental evidence for the clinical application of JPYZXZ in the treatment of GC via PD-L1.
    Keywords:  PD-L1; exosomes; gastric cancer; myeloid-derived suppressor cells; traditional Chinese medicine; tumor microenvironment
  42. J Exp Clin Cancer Res. 2023 Aug 22. 42(1): 216
      BACKGROUND: In addition to specifically inducing tumor cell apoptosis, recombinant tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has also been reported to influence the cancer immune microenvironment; however, its underlying effects and mechanisms remain unclear. Investigating the immunomodulatory effects and mechanisms of recombinant TRAIL in the tumor microenvironment (TME) may provide an important perspective and facilitate the exploration of novel TRAIL strategies for tumor therapy.METHODS: Immunocompetent mice with different tumors were treated with three doses of recombinant TRAIL, and then the tumors were collected for immunological detection and mechanistic investigation. Methodological approaches include flow cytometry analysis and single-cell sequencing.
    RESULTS: In an immunocompetent mouse model, recombinant soluble mouse TRAIL (smTRAIL) had dose-related immunomodulatory effects. The optimal dose of smTRAIL (2 mg/kg) activated innate immune cells and CD8+ T cells, whereas higher doses of smTRAIL (8 mg/kg) promoted the formation of a tumor-promoting immune microenvironment to counteract the apoptotic effects on tumor cells. The higher doses of smTRAIL treatment promoted M2-like macrophage recruitment and polarization and increased the production of protumor inflammatory cytokines, such as IL-10, which deepened the suppression of natural killer (NK) cells and CD8+ T cells in the tumor microenvironment. By constructing an HU-HSC-NPG.GM3 humanized immune system mouse model, we further verified the immunomodulatory effects induced by recombinant soluble human TRAIL (shTRAIL) and found that combinational administration of shTRAIL and trabectedin, a macrophage-targeting drug, could remodel the tumor immune microenvironment, further enhance antitumor immunity, and strikingly improve antitumor effects.
    CONCLUSION: Our results highlight the immunomodulatory role of recombinant TRAIL and suggest promising therapeutic strategies for clinical application.
    Keywords:  Immunoregulation; TRAIL; Tumor-associated macrophage
  43. Int J Mol Sci. 2023 Aug 11. pii: 12681. [Epub ahead of print]24(16):
      Despite the advances made in treatment, the prognosis of pancreatic ductal adenocarcinoma (PDAC) remains dismal, even in the locoregional and locally advanced stages, with high relapse rates after surgery. PDAC exhibits a chemoresistant and immunosuppressive phenotype, and the tumor microenvironment (TME) surrounding cancer cells actively participates in creating a stromal barrier to chemotherapy and an immunosuppressive environment. Recently, there has been an increasing use of interventional radiology techniques for the treatment of PDAC, although they do not represent a standard of care and are not included in clinical guidelines. Local approaches such as radiation therapy, hyperthermia, microwave or radiofrequency ablation, irreversible electroporation and high-intensity focused ultrasound exert their action on the tumor tissue, altering the composition and structure of TME and potentially enhancing the action of chemotherapy. Moreover, their action can increase antigen release and presentation with T-cell activation and reduction tumor-induced immune suppression. This review summarizes the current evidence on locoregional therapies in PDAC and their effect on remodeling TME to make it more susceptible to the action of antitumor agents.
    Keywords:  ablation therapies; locoregional treatments; pancreatic cancer; radiotherapy; tumor microenvironment
  44. Cell Oncol (Dordr). 2023 Aug 23.
      BACKGROUND: In recent years, the significance of the nervous system in the tumor microenvironment has gained increasing attention. The bidirectional communication between nerves and cancer cells plays a critical role in tumor initiation and progression. Perineural invasion (PNI) occurs when tumor cells invade the nerve sheath and/or encircle more than 33% of the nerve circumference. PNI is a common feature in various malignancies and is associated with tumor invasion, metastasis, cancer-related pain, and unfavorable clinical outcomes. The colon and rectum are highly innervated organs, and accumulating studies support PNI as a histopathologic feature of colorectal cancer (CRC). Therefore, it is essential to investigate the role of nerves in CRC and comprehend the mechanisms of PNI to impede tumor progression and improve patient survival.CONCLUSION: This review elucidates the clinical significance of PNI, summarizes the underlying cellular and molecular mechanisms, introduces various experimental models suitable for studying PNI, and discusses the therapeutic potential of targeting this phenomenon. By delving into the intricate interactions between nerves and tumor cells, we hope this review can provide valuable insights for the future development of CRC treatments.
    Keywords:  Colorectal innervation; Neurotrophins; Perineural invasion; Prognosis; Tumor microenvironment
  45. Antioxid Redox Signal. 2023 Aug 19.
      SIGNIFICANCE: Cancer is a complex and heterotypic structure with a spatial organization that contributes to challenges in therapeutics. Enzymes associated with producing the gasotransmitter hydrogen sulfide (H2S) are differentially expressed in tumors. Indeed, critical and paradoxical roles have been attributed to H2S in cancer-promoting characteristics by targeting both cancer cells and their milieu. This review focuses on the evidence and knowledge gaps of H2S on the tumor redox microenvironment and the pharmacological effects of H2S donors on cancer biology.RECENT ADVANCES: Endogenous and pharmacological concentrations of H2S evoke different effects on the same cell type: physiological H2S concentrations have been associated with tumor development and progression. In contrast pharmacological concentrations have been associated with anti-cancer effects.
    CRITICAL ISSUES: The exact threshold between the promotion and inhibition of tumorigenesis by H2S is largely unknown. The main issues covered in this review include H2S-modulated signaling pathways that are critical for cancer cells, the potential effects of H2S on cellular components of the tumor microenvironment, temporal modulation of H2S in promoting or inhibiting tumor progression (similar to observed for inflammation), and pharmacological agents that modulate H2S and which could play a role in antineoplastic therapy.
    FUTURE DIRECTIONS: Given the complexity and heterogeneity of tumor composition, mechanistic studies on context-dependent pharmacological effects of H2S donors for cancer therapy are necessary. These studies must determine the critical signaling pathways and the cellular components involved to allow advances in the rational use of H2S donors as antineoplastic agents.
  46. Cancers (Basel). 2023 Aug 17. pii: 4145. [Epub ahead of print]15(16):
      The tumor stroma, or the microenvironment surrounding solid tumors, can significantly impact the effectiveness of cancer therapies. The tumor microenvironment is characterized by high interstitial pressure, a consequence of leaky vasculature, and dense stroma created by excessive deposition of various macromolecules such as collagen, fibronectin, and hyaluronic acid (HA). In addition, non-cancerous cells such as cancer-associated fibroblasts (CAFs) and the extracellular matrix (ECM) itself can promote tumor growth. In recent years, there has been increased interest in combining standard cancer treatments with stromal-targeting strategies or stromal modulators to improve therapeutic outcomes. Furthermore, the use of nanomedicine, which can improve the delivery and retention of drugs in the tumor, has been proposed to target the stroma. This review focuses on how different stromal components contribute to tumor progression and impede chemotherapeutic delivery. Additionally, this review highlights recent advancements in nanomedicine-based stromal modulation and discusses potential future directions for developing more effective stroma-targeted cancer therapies.
    Keywords:  cancer therapy; cancer-associated fibroblasts; collagen; extracellular matrix; fibronectin; hyaluronic acid; nanomedicine; tumor microenvironment
  47. Inflamm Bowel Dis. 2023 Aug 25. pii: izad113. [Epub ahead of print]
      Exosomes are considered a mediator of communication within the tumor microenvironment (TME), which modulates cancer progression through transmitting cargos between cancer cells and other cancer-related cells in TME. Circular RNAs (circRNAs) have emerged to be regulators in colorectal cancer (CRC) progression, but most of them have not been discussed in CRC. This study aims to investigate the role of circRNA aspartate beta-hydroxylase (circASPH) in CRC progression and its correlation with exosome-mediated TME. At first, we determined that circASPH was upregulated in CRC samples and cell lines. Functionally, the circASPH deficiency suppressed the malignant processes of CRC cells and also inhibited in vivo tumor growth via enhancing antitumor immunity. Mechanically, circASPH facilitated macrophage M2 polarization by upregulating exosomal stimulator of interferon genes (STING). CircASPH interacted with insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) to stabilize IGF2BP2 protein, therefore enhancing the stability of m6A-modified STING mRNA. In turn, coculture of STING-overexpressed macrophages recovered the suppression of silenced circASPH on the malignancy of CRC cells both in vitro and in vivo. Our study demonstrated that circASPH enhances exosomal STING to facilitate M2 macrophage polarization, which further accelerates CRC progression. The findings support circASPH as a promising therapeutic target for CRC treatment.
    Keywords:  STING; circASPH; colorectal cancer; exosome; macrophage polarization
  48. J Immunother Cancer. 2023 08;pii: e007441. [Epub ahead of print]11(8):
      BACKGROUND: Although immune checkpoint blockade (ICB) therapy has shown remarkable benefits in cancers, a subset of patients with cancer exhibits unresponsiveness or develop acquired resistance due to the existence of abundant immunosuppressive cells. Tumor-associated macrophages (TAMs), as the dominant immunosuppressive population, impede the antitumor immune response; however, the underlying mechanisms have not been fully elucidated yet.METHODS: Single-cell RNA sequencing analysis was performed to portray macrophage landscape and revealed the underlying mechanism of component 1q (C1q)+ TAMs. Malignant pleural effusion (MPE) of human and mouse was used to explore the phenotypes and functions of C1q+ TAMs.
    RESULTS: C1q+ TAMs highly expressed multiple inhibitory molecules and their high infiltration was significantly correlated with poor prognosis. C1q+ TAMs promote MPE immunosuppression through impairing the antitumor effects of CD8+ T cells. Mechanistically, C1q+ TAMs enhance fatty acid binding protein 5 (FABP5)-mediated fatty acid metabolism, which activate transcription factor peroxisome proliferator-activated receptor-gamma, increasing the gene expression of inhibitory molecules. A high-fat diet increases the expression of inhibitory molecules in C1q+ TAMs and the immunosuppression of MPE microenvironment, whereas a low-fat diet ameliorates these effects. Moreover, FABP5 inhibition represses the expression of inhibitory molecules in TAMs and tumor progression, while enhancing the efficacy of ICB therapy in MPE and lung cancer.
    CONCLUSIONS: C1q+ TAMs impede antitumor effects of CD8+ T cells promoting MPE immunosuppression. Targeting C1q+ TAMs effectively alleviates the immunosuppression and enhances the efficacy of ICB therapy. C1q+ TAMs subset has great potential to be a therapeutic target for cancer immunotherapy.
    Keywords:  immunomodulation; immunotherapy; lymphocytes, tumor-infiltrating; macrophages; tumor microenvironment
  49. Cancer Lett. 2023 Aug 17. pii: S0304-3835(23)00306-3. [Epub ahead of print] 216355
      Chimeric antigen receptor (CAR)-T cell immunotherapy is highly effective against hematological neoplasms. However, owing to tumor variability, low antigen specificity, and impermanent viability of CAR-T cells, their use in the treatment of solid tumors is limited. Here, a novel CAR-T cell targeting B7-H3 and incorporating a 4-1BB costimulatory molecule with STAT3-and STAT5-related activation motifs was constructed using lentivirus transduction. B7-H3, a tumor-associated antigen, and its scFv antibody endowed CAR-T cells with tumor-specific targeting capabilities. Moreover, the integration of the trIL2RB and YRHQ motifs stimulated STAT5 and STAT3 in an antigen-dependent manner, inducing a remarkable increase in the proliferation and survival of CAR-T cells via the activation of the JAK-STAT signaling pathway. Besides, the proportion of less-differentiated T cells increased among BB-trIL2RB-z(YRHQ) CAR-T cells. Moreover, BB-trIL2RB-z(YRHQ) effectively inhibited ovarian cancer (OC) and triple-negative breast cancer (TNBC) in vivo at low doses, without high serum levels of inflammatory cytokines and organ toxicity. Therefore, our study proposes a combination of elements for the construction of superior pluripotent CAR-T cells to provide an effective strategy for the treatment of intractable solid tumors.
    Keywords:  CD276; Chimeric antigen receptor; Immunotherapy; JAK-STAT; Solid tumor