bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2023‒12‒24
35 papers selected by
Peio Azcoaga, Biodonostia HRI

  1. Trends Cancer. 2023 Dec 22. pii: S2405-8033(23)00238-8. [Epub ahead of print]
      The tumor microenvironment (TME) contains a complex cellular ecosystem where cancer, stromal, vascular, and immune cells interact. Macrophages and regulatory T cells (Tregs) are critical not only for maintaining immunological homeostasis and tumor growth but also for monitoring the functional states of other immune cells. Emerging evidence reveals that metabolic changes in macrophages and Tregs significantly influence their pro-/antitumor functions through the regulation of signaling cascades and epigenetic reprogramming. Hence, they are increasingly recognized as therapeutic targets in cancer immunotherapy. Specific metabolites in the TME may also affect their pro-/antitumor functions by intervening with the metabolic machinery. We discuss how metabolites influence the immunosuppressive phenotypes of tumor-associated macrophages (TAMs) and Tregs. We then describe how TAMs and Tregs, independently or collaboratively, utilize metabolic mechanisms to suppress the activity of CD8+ T cells. Finally, we highlight promising metabolic interventions that can improve the outcome of current cancer therapies.
    Keywords:  cancer immunotherapy; immunometabolism; immunosuppression; macrophage; regulatory T cell; tumor microenvironment
  2. Cancer Treat Res. 2023 ;190 3-24
      RNA modifications have recently been recognized as essential posttranscriptional regulators of gene expression in eukaryotes. Investigations over the past decade have revealed that RNA chemical modifications have profound effects on tumor initiation, progression, refractory, and recurrence. Tumor cells are notorious for their robust plasticity in response to the stressful microenvironment and undergo metabolic adaptations to sustain rapid cell proliferation, which is termed as metabolic reprogramming. Meanwhile, cancer-associated metabolic reprogramming leads to substantial alterations of intracellular and extracellular metabolites, which further reshapes the tumor microenvironment (TME). Moreover, cancer cells compete with tumor-infiltrating immune cells for the limited nutrients to maintain their proliferation and function in the TME. In this chapter, we review recent interesting findings on the engagement of epitranscriptomic pathways, especially the ones associated with N6-methyladenosine (m6A), in the regulation of cancer metabolism and the surrounding microenvironment. We also discuss the promising therapeutic approaches targeting RNA modifications for anti-tumor therapy.
    Keywords:  Aerobic glycolysis; Amino acid metabolism; Cancer metabolism; Immune cells; Immunotherapy; Lipid metabolism; RNA modification; Tumor microenvironment; m6A
  3. Front Oncol. 2023 ;13 1288383
      Chimeric antigen receptor (CAR-T) cell therapy has been widely used in hematological malignancies and has achieved remarkable results, but its long-term efficacy in solid tumors is greatly limited by factors such as the tumor microenvironment (TME). In this paper, we discuss the latest research and future views on CAR-T cell cancer immunotherapy, compare the different characteristics of traditional immunotherapy and CAR-T cell therapy, introduce the latest progress in CAR-T cell immunotherapy, and analyze the obstacles that hinder the efficacy of CAR-T cell therapy, including immunosuppressive factors, metabolic energy deficiency, and physical barriers. We then further discuss the latest therapeutic strategies to overcome these barriers, as well as management decisions regarding the possible safety issues of CAR-T cell therapy, to facilitate solutions to the limited use of CAR-T immunotherapy.
    Keywords:  CAR-T; cancer immunotherapy; immune checkpoint; immunosuppressive environment; tumor microenvironment
  4. Int J Mol Sci. 2023 Dec 15. pii: 17536. [Epub ahead of print]24(24):
      Similarly to our healthy organs, the tumor tissue also constitutes an ecosystem. This implies that stromal cells acquire an altered phenotype in tandem with tumor cells, thereby promoting tumor survival. Cancer cells are fueled by abnormal blood vessels, allowing them to develop and proliferate. Tumor-associated fibroblasts adapt their cytokine and chemokine production to the needs of tumor cells and alter the peritumoral stroma by generating more collagen, thereby stiffening the matrix; these processes promote epithelial-mesenchymal transition and tumor cell invasion. Chronic inflammation and the mobilization of pro-tumorigenic inflammatory cells further facilitate tumor expansion. All of these events can impede the effective administration of tumor treatment; so, the successful inhibition of tumorous matrix remodeling could further enhance the success of antitumor therapy. Over the last decade, significant progress has been made with the introduction of novel immunotherapy that targets the inhibitory mechanisms of T cell activation. However, extensive research is also being conducted on the stromal components and other cell types of the tumor microenvironment (TME) that may serve as potential therapeutic targets.
    Keywords:  angiogenesis; extracellular matrix; immune checkpoint inhibitors; proteoglycans; tumor immunity; tumor microenvironment; tumor stroma; tumor-associated fibroblasts
  5. Biochim Biophys Acta Rev Cancer. 2023 Dec 13. pii: S0304-419X(23)00200-7. [Epub ahead of print] 189051
      This review delves into the most recent research on the metabolic adaptability of cancer cells and examines how their metabolic functions can impact their progression into metastatic forms. We emphasize the growing significance of lipid metabolism and dietary lipids within the tumor microenvironment, underscoring their influence on tumor progression. Additionally, we present an outline of the interplay between metabolic processes and the epigenome of cancer cells, underscoring the importance regarding the metastatic process. Lastly, we examine the potential of targeting metabolism as a therapeutic approach in combating cancer progression, shedding light on innovative drugs/targets currently undergoing preclinical evaluation.
    Keywords:  Epigenetics; Lipid metabolism; Metastasis; Microenvironment; Therapies
  6. Curr Issues Mol Biol. 2023 Dec 05. 45(12): 9753-9767
      Malignant tumors exhibit rapid growth and high metabolic rates, similar to embryonic stem cells, and depend on aerobic glycolysis, known as the "Warburg effect". This understanding has enabled the use of radiolabeled glucose analogs in tumor staging and therapeutic response assessment via PET scans. Traditional treatments like chemotherapy and radiotherapy target rapidly dividing cells, causing significant toxicity. Despite immunotherapy's impact on solid tumor treatment, gaps remain, leading to research on cancer cell evasion of immune response and immune tolerance induction via interactions with the tumor microenvironment (TME). The TME, consisting of immune cells, fibroblasts, vessels, and the extracellular matrix, regulates tumor progression and therapy responses. TME-targeted therapies aim to transform this environment from supporting tumor growth to impeding it and fostering an effective immune response. This review examines the metabolic disparities between immune cells and cancer cells, their impact on immune function and therapeutic targeting, the TME components, and the complex interplay between cancer cells and nontumoral cells. The success of TME-targeted therapies highlights their potential to achieve better cancer control or even a cure.
    Keywords:  immunotherapy; oncometabolites; tumor microenvironment
  7. Biomedicines. 2023 Dec 16. pii: 3326. [Epub ahead of print]11(12):
      As an immune checkpoint molecule, CD200 serves a foundational role in regulating immune homeostasis and promoting self-tolerance. While CD200 expression occurs in various immune cell subsets and normal tissues, its aberrant expression patterns in hematologic malignancies and solid tumors have been linked to immune evasion and cancer progression under pathological conditions, particularly through interactions with its cognate receptor, CD200R. Through this CD200/CD200R signaling pathway, CD200 exerts its immunosuppressive effects by inhibiting natural killer (NK) cell activation, cytotoxic T cell functions, and M1-polarized macrophage activity, while also facilitating expansion of myeloid-derived suppressor cells (MDSCs) and Tregs. Moreover, CD200/CD200R expression has been linked to epithelial-to-mesenchymal transition and distant metastasis, further illustrating its role in cancer progression. Conversely, CD200 has also been shown to exert anti-tumor effects in certain cancer types, such as breast carcinoma and melanoma, indicating that CD200 may exert bidirectional effects on cancer progression depending on the specific tumor microenvironment (TME). Regardless, modulating the CD200/CD200R axis has garnered clinical interest as a potential immunotherapeutic strategy for cancer therapy, as demonstrated by early-phase clinical trials. However, further research is necessary to fully understand the complex interactions of CD200 in the tumor microenvironment and to optimize its therapeutic potential in cancer immunotherapy.
    Keywords:  CD200; CD200R; cancer; checkpoint; immunosuppressive signaling; therapy; tumor immune microenvironment
  8. Int J Mol Sci. 2023 Dec 13. pii: 17422. [Epub ahead of print]24(24):
      The occurrence and development of tumors require the metabolic reprogramming of cancer cells, namely the alteration of flux in an autonomous manner via various metabolic pathways to meet increased bioenergetic and biosynthetic demands. Tumor cells consume large quantities of nutrients and produce related metabolites via their metabolism; this leads to the remodeling of the tumor microenvironment (TME) to better support tumor growth. During TME remodeling, the immune cell metabolism and antitumor immune activity are affected. This further leads to the escape of tumor cells from immune surveillance and therefore to abnormal proliferation. This review summarizes the regulatory functions associated with the abnormal biosynthesis and activity of metabolic signaling molecules during the process of tumor metabolic reprogramming. In addition, we provide a comprehensive description of the competition between immune cells and tumor cells for nutrients in the TME, as well as the metabolites required for tumor metabolism, the metabolic signaling pathways involved, and the functionality of the immune cells. Finally, we summarize current research targeted at the development of tumor immunotherapy. We aim to provide new concepts for future investigations of the mechanisms underlying the metabolic reprogramming of tumors and explore the association of these mechanisms with tumor immunity.
    Keywords:  immune cells; tumor immunity; tumor metabolism; tumor microenvironment; tumor therapy
  9. Cancer Immunol Res. 2023 Dec 21. OF1-OF5
      Immune cells in the tumor niche robustly influence disease progression. Remarkably, in cancer, developmental pathways are reenacted. Many parallels between immune regulation of embryonic development and immune regulation of tumor progression can be drawn, with evidence clearly supporting an immune-suppressive microenvironment in both situations. In these ecosystems, metabolic and bioenergetic circuits guide and regulate immune cell differentiation, plasticity, and functional properties of suppressive and inflammatory immune subsets. As such, there is an emerging pattern of intersection across the dynamic process of ontogeny and the ever-evolving tumor neighborhood. In this article, we focus on the convergence of immune programming during ontogeny and in the tumor microenvironment. Exemplifying dysregulation of Hedgehog (Hh) activity, a key player during ontogeny, we highlight a critical convergence of these fields and the metabolic axis of the nutrient sensing hexosamine biosynthetic pathway (HBP) that integrates glucose, glutamine, amino acids, acetyl CoA, and uridine-5'-triphosphate (UTP), culminating in the synthesis of UDP-GlcNAc, a metabolite that functions as a metabolic and bioenergetic sensor. We discuss an emerging pattern of immune regulation, orchestrated by O-GlcNAcylation of key transcriptional regulators, spurring suppressive activity of dysfunctional immune cells in the tumor microenvironment.
  10. Front Immunol. 2023 ;14 1288273
      Cancer immunotherapy has developed rapidly in recent years and stands as one of the most promising techniques for combating cancer. To develop and optimize cancer immunotherapy, it is crucial to comprehend the interactions between immune cells and tumor cells in the tumor microenvironment (TME). The TME is complex, with the distribution and function of immune cells undergoing dynamic changes. There are several research techniques to study the TME, and intravital imaging emerges as a powerful tool for capturing the spatiotemporal dynamics, especially the movement behavior and the immune function of various immune cells in real physiological state. Intravital imaging has several advantages, such as high spatio-temporal resolution, multicolor, dynamic and 4D detection, making it an invaluable tool for visualizing the dynamic processes in the TME. This review summarizes the workflow for intravital imaging technology, multi-color labeling methods, optical imaging windows, methods of imaging data analysis and the latest research in visualizing the spatio-temporal dynamics and function of immune cells in the TME. It is essential to investigate the role played by immune cells in the tumor immune response through intravital imaging. The review deepens our understanding of the unique contribution of intravital imaging to improve the efficiency of cancer immunotherapy.
    Keywords:  cancer immunotherapy; immune cells; intravital imaging; movement behavior; spatio-temporal information; tumor microenvironment
  11. Mol Oncol. 2023 Dec 19.
      Glucose catabolism, one of the essential pathways sustaining cellular bioenergetics, has been widely studied in the context of tumors. Nevertheless, the function of various branches of glucose metabolism that stem from 'classical' glycolysis have only been partially explored. This review focuses on discussing general mechanisms and pathological implications of glycolysis and its branching pathways in the biology of B cell malignancies. We summarize here what is known regarding pentose phosphate, hexosamine, serine biosynthesis and glycogen synthesis pathways in this group of tumors. Despite most findings have been based on malignant B cells themselves, we also discuss the role of glucose metabolism in the tumor microenvironment, with a focus on T cells. Understanding the contribution of glycolysis branching pathways and how they are hijacked in B cell malignancies will help to dissect the role they have in sustaining the dissemination and proliferation of tumor B cells and regulating immune responses within these tumors. Ultimately, this should lead to deciphering associated vulnerabilities and improve current therapeutic schedules.
    Keywords:  B cells; T cells; glucose metabolism; tumor microenvironment
  12. Small. 2023 Dec 21. e2308639
      Next-generation cancer treatments are expected not only to target cancer cells but also to simultaneously train immune cells to combat cancer while modulating the immune-suppressive environment of tumors and hosts to ensure a robust and lasting response. Achieving this requires carriers that can codeliver multiple therapeutics to the right cancer and/or immune cells while ensuring patient safety. Nanotechnology holds great potential for addressing these challenges. This article highlights the recent advances in nanoimmunotherapeutic development, with a focus on breast cancer. While immune checkpoint inhibitors (ICIs) have achieved remarkable success and lead to cures in some cancers, their response rate in breast cancer is low. The poor response rate in solid tumors is often associated with the low infiltration of anti-cancer T cells and an immunosuppressive tumor microenvironment (TME). To enhance anti-cancer T-cell responses, nanoparticles are employed to deliver ICIs, bispecific antibodies, cytokines, and agents that induce immunogenic cancer cell death (ICD). Additionally, nanoparticles are used to manipulate various components of the TME, such as immunosuppressive myeloid cells, macrophages, dendritic cells, and fibroblasts to improve T-cell activities. Finally, this article discusses the outlook, challenges, and future directions of nanoimmunotherapeutics.
    Keywords:  breast cancer; immunosuppression; immunotherapy; nanoparticle; tumor microenvironment
  13. Cell Signal. 2023 Dec 15. pii: S0898-6568(23)00426-6. [Epub ahead of print] 111011
      Prostate cancer is among the most common malignancies for men, with limited therapy options for last stages of the tumor. There are some different options for treatment and control of prostate tumor growth. However, targeting some specific molecules and cells within tumors has been attracted interests in recent years. The tumor microenvironment (TME) has an important role in the initiation of various malignancies, which can also expand the progression of tumor and facilitate invasion of malignant cells. By regulating immune responses and distinct changes in the metabolism of cells in the tumor, TME has substantial effects in the resistance of cancer cells to therapy. TME in various solid cancers like prostate cancer includes various cells, including cancer cells, supportive stromal cells, immunosuppressive cells, and anticancer inflammatory cells. Natural products including herbal-derived agents and also other natural compounds have been well studied for their anti-tumor potentials. These compounds may modulate various signaling pathways involved in TME, such as immune responses, the metabolism of cells, epigenetics, angiogenesis, and extracellular matrix (ECM). This paper provides a review of the current knowledge of prostate TME and complex interactions in this environment. Additionally, the potential use of natural products and also nanoparticles loaded with natural products as therapeutic adjuvants on different cells and therapeutic targets within prostate TME will be discussed.
    Keywords:  CD8+ T lymphocytes; Nanoparticles; Natural products; Prostate Cancer; Tumor microenvironment (TME)
  14. Cell Transplant. 2023 Jan-Dec;32:32 9636897231220073
      The role of mesenchymal stem cells (MSCs) in the breast tumor microenvironment (TME) is significant and multifaceted. MSCs are recruited to breast tumor sites through molecular signals released by tumor sites. Once in the TME, MSCs undergo polarization and interact with various cell populations, including immune cells, cancer-associated fibroblasts (CAFs), cancer stem cells (CSCs), and breast cancer cells. In most cases, MSCs play roles in breast cancer therapeutic resistance, but there is also evidence that indicates their abilities to sensitize cancer cells to chemotherapy and radiotherapy. MSCs possess inherent regenerative and homing properties, making them attractive candidates for cell-based therapies. Therefore, MSCs can be engineered to express therapeutic molecules or deliver anti-cancer agents directly to tumor sites. Unraveling the intricate relationship between MSCs and the breast TME has the potential to uncover novel therapeutic targets and advance our understanding of breast cancer biology.
    Keywords:  breast cancer; mesenchymal stem cells; tumor microenvironment
  15. Surg Oncol. 2023 Dec 18. pii: S0960-7404(23)00131-7. [Epub ahead of print]52 102031
      Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) comprise the two most common primary liver malignancies. Curative treatment options often include hepatectomy or liver transplantation; however, many patients present with advanced disease that is not amenable to surgical management. In turn, many patients are treated with systemic or targeted therapy. The tumor microenvironment (TME) is a complex network of immune cells and somatic cells, which can foster an environment for disease development and progression, as well as susceptibility and resistance to systemic therapeutic agents. In particular, the TME is comprised of both immune and non-immune cells. Immune cells such as T lymphocytes, natural killer (NK) cells, macrophages, and neutrophils reside in the TME and can affect tumorigenesis, disease progression, as well as response to therapy. Given the importance of the immune system, there are many emerging approaches for cancer immunotherapy. We herein provide a review the latest data on immunotherapy for primary HCC and BTC relative to the TME.
    Keywords:  Hepatic malignancies; Immune checkpoint inhibitors; Immunotherapy
  16. Cell Rep. 2023 Dec 13. pii: S2211-1247(23)01572-3. [Epub ahead of print]42(12): 113560
      Tumor-associated myeloid cells modulate the tumor microenvironment and affect tumor progression. Type I interferon (IFN-I) has multiple effects on tumors and immune response, and ubiquitin-specific peptidase 18 (USP18) functions as a negative regulator of IFN-I signal transduction. This study aims to examine the function of IFN-I in myeloid cells during tumor progression. Here, we show that deletion of USP18 in myeloid cells suppresses tumor progression. Enhanced IFN-I signaling and blocked USP18 expression prompt downregulation of colony stimulating factor 1 receptor (CSF1R) and polarization of tumor-associated macrophages toward pro-inflammatory phenotypes. Further in vitro experiments reveal that downregulation of CSF1R is mediated by ubiquitin-proteasome degradation via E3 ligase neural precursor cell-expressed, developmentaly downregulated 4 (NEDD4) and the IFN-induced increase in ubiquitin E2 ubiquitin-conjugating enzyme H5. USP18 impairs ubiquitination and subsequent degradation of CSF1R by interrupting NEDD4 binding to CSF1R. These results reveal a previously unappreciated role of IFN-I in macrophage polarization by regulating CSF1R via USP18 and suggest targeting USP18 in myeloid-lineage cells as an effective strategy for IFN-based therapies.
    Keywords:  CP: Cancer; CSF1R; NEDD4; USP18; macrophage polarization; tumor microenvironment; tumor-associated macrophages; type I interferon; ubiquitination
  17. J Immunol. 2023 Dec 20. pii: ji2300256. [Epub ahead of print]
      Macrophages represent the most abundant immune component of the tumor microenvironment and often exhibit protumorigenic (M2-like) phenotypes that contribute to disease progression. Despite their generally accepted protumorigenic role, macrophages can also display tumoricidal (or M1-like) behavior, revealing that macrophages can be functionally reprogrammed, depending on the cues received within the tumor microenvironment. Moreover, such plasticity may be achieved by pharmacologic or biologic interventions. To that end, we previously demonstrated that a novel immunomodulator termed the "very small size particle" (VSSP) facilitates maturation of dendritic cells and differentiation of myeloid-derived suppressor cells to APCs with reduced suppressive activity in cancer models. VSSP was further shown to act in the bone marrow to drive the differentiation of progenitors toward monocytes, macrophages, and dendritic cells during emergency myelopoiesis. However, the underlying mechanisms for VSSP-driven alterations in myeloid differentiation and function remained unclear. In this study, in mouse models, we focused on macrophages and tested the hypothesis that VSSP drives macrophages toward M1-like functional states via IRF8- and PU.1-dependent mechanisms. We further hypothesized that such VSSP-mediated actions would be accompanied by enhanced antitumor responses. Overall, we showed that (1) VSSP drives naive or M2-derived macrophages to M1-like states, (2) the M1-like state induced by VSSP occurs via IRF8- and PU.1-dependent mechanisms, and (3) single-agent VSSP induces an antitumor response that is accompanied by alterations in the intratumoral myeloid compartment. These results provide a deeper mechanistic underpinning of VSSP and strengthen its use to drive M1-like responses in host defense, including cancer.
  18. Biochim Biophys Acta Rev Cancer. 2023 Dec 17. pii: S0304-419X(23)00207-X. [Epub ahead of print] 189058
      Ovarian cancer is a less common tumor in women compared to cervical or breast cancer, however it is more malignant and has worse outcomes. Ovarian cancer patients still have a five-year survival rate < 50% despite advances in therapy. Due to recent developments in immune checkpoint inhibitors (ICIs), cancer immunotherapy has attracted increased interest. Pyroptosis is a highly inflammatory form of cell death, which is essential for bridging innate and adaptive immunity, and is involved in immune regulation within the tumor microenvironment (TME). Recent research has shown that pyroptosis can promote immunotherapy of ovarian cancer, including treatment with chimeric antigen receptor T-cells (CAR-T) or ICIs. Moreover, inflammasomes, various signaling pathways and lncRNAs can all affect pyroptosis in ovarian cancer. Here we discuss how pyroptosis affects the development and progression of ovarian cancer as well as the TME. We also provide a summary of small molecule drugs that could target pyroptotic cell death processes and may be useful in ovarian cancer therapy.
    Keywords:  Gasdermin D; Immune checkpoint inhibitors; Inflammasomes: Tumor microenvironment; Inflammatory cell death; Programmed cell death
  19. Proc Natl Acad Sci U S A. 2023 Dec 26. 120(52): e2311460120
      The TP53 gene is mutated in approximately 30% of all breast cancer cases. Adipocytes and preadipocytes, which constitute a substantial fraction of the stroma of normal mammary tissue and breast tumors, undergo transcriptional, metabolic, and phenotypic reprogramming during breast cancer development and play an important role in tumor progression. We report here that p53 loss in breast cancer cells facilitates the reprogramming of preadipocytes, inducing them to acquire a unique transcriptional and metabolic program that combines impaired adipocytic differentiation with augmented cytokine expression. This, in turn, promotes the establishment of an inflammatory tumor microenvironment, including increased abundance of Ly6C+ and Ly6G+ myeloid cells and elevated expression of the immune checkpoint ligand PD-L1. We also describe a potential gain-of-function effect of common p53 missense mutations on the inflammatory reprogramming of preadipocytes. Altogether, our study implicates p53 deregulation in breast cancer cells as a driver of tumor-supportive adipose tissue reprogramming, expanding the network of non-cell autonomous mechanisms whereby p53 dysfunction may promote cancer. Further elucidation of the interplay between p53 and adipocytes within the tumor microenvironment may suggest effective therapeutic targets for the treatment of breast cancer patients.
    Keywords:  adipocytes; breast cancer; p53; preadipocytes
  20. Biology (Basel). 2023 Dec 15. pii: 1531. [Epub ahead of print]12(12):
      Breast cancer is the leading cause of cancer-related death in women worldwide. It is well known that breast cancer shows significant alterations in the tumor microenvironment (TME), which is composed of a variety of immune cells, including natural killer (NK) cells, that have a key role in tumor development or anti-tumor responses in breast cancer patients. Luminal B (BT474) and triple-negative breast cancer (HS578T) cell lines were cultured in 2D and 3D model systems. PMBCs from healthy donors were isolated and treated with extracellular vesicles (EVs) from monolayer and spheroids of BT474 and HS578T and analyzed using cytofluorimetric approaches. We observed that EVs can alter the activation and presence of CD335+/CD11b+ NK cells. EVs derived from BT474 and HS578T cells trigger the activation and, simultaneously, a reduction in the percentage of CD335+/CD11b+ NK cells. In addition, EVs derived from BT474 also significantly reduce CD39+ T-regulatory (T-reg) cells. Our preliminary data suggest that using EVs to treat tumors could potentially alter components of the immune system, which causes hyperactivation of specific cell types and can lead to aggressive growth. These data will guide the designing of new personalized diagnostic approaches based on in-depth study of the TME.
    Keywords:  anti-cancer immunity; breast cancer; extracellular vesicles; innovative diagnostic approach; personalized medicine; spheroids; tumor microenvironment
  21. Front Immunol. 2023 ;14 1340844
    Keywords:  autophagy; colorectal cancer immunotherapy; immune microenvironment; immunotherapy; radiotherapy; represented by immune checkpoint inhibitors (ICIs)
  22. J Cell Sci. 2023 Dec 18. pii: jcs.261145. [Epub ahead of print]
      Cellular heterogeneity and extracellular matrix (ECM) stiffening have been shown to be drivers of breast cancer invasiveness. Here we examined how stiffness-dependent crosstalk between cancer cells and mesenchymal stem cells (MSCs) within an evolving tumor microenvironment (TME) regulates cancer invasion. By analyzing previously published single-cell RNAseq datasets, we establish the existence of a sub-population co-expressing MSC and cancer associated fibroblast (CAF) markers in highly aggressive triple-negative breast cancers (TNBCs) in primary tumor, secondary sites, and in circulatory tumor cell clusters. Using 0.5, 2 and 5 kPa hydrogels mimicking different stages of ECM stiffening, we show that on pre-metastatic stroma mimetic 2 kPa gels, conditioned media secreted by MDA-MB-231 TNBC cells drives efficient MSC chemotaxis and induces stable CAF differentiation in a TGFβ/contractility-dependent manner. In addition to enhancing cancer cell proliferation, 2 kPa CAFs maximally boost local invasion and confer resistance to flow-induced shear stresses. Collectively, our results suggest that homing of MSCs at the pre-metastatic stage and their differentiation into CAFs actively drives breast cancer invasion and metastasis in TNBCs.
    Keywords:  Cancer associated fibroblast (CAF); Cancer invasion; Differentiation; ECM stiffness; Mesenchymal stem cells (MSCs); Shear stress; TGFβ; scRNAseq analysis
  23. Front Immunol. 2023 ;14 1269896
      Nicotinamide adenine dinucleotide (NAD+) is indispensable for various oxidation-reduction reactions in mammalian cells, particularly during energy production. Malignant cells increase the expression levels of NAD+ biosynthesis enzymes for rapid proliferation and biomass production. Furthermore, mounting proof has indicated that NAD-degrading enzymes (NADases) play a role in creating the immunosuppressive tumor microenvironment (TME). Interestingly, both inhibiting NAD+ synthesis and targeting NADase have positive implications for cancer treatment. Here we summarize the detrimental outcomes of increased NAD+ production, the functions of NAD+ metabolic enzymes in creating an immunosuppressive TME, and discuss the progress and clinical translational potential of inhibitors for NAD+ synthesis and therapies targeting NADase.
    Keywords:  CD38; NAD+ metabolism; NAMPT inhibitor; cancer immunotherapy; cancer treatment; tumor microenvironment
  24. bioRxiv. 2023 Dec 06. pii: 2023.12.06.570444. [Epub ahead of print]
      Immune cells in the tumor microenvironment are not only powerful regulators of immunosuppression and tumorigenesis, but also represent a dominant cell type, with tumor-associated macrophages (TAMs) comprising up to 50% of total cell mass in solid tumors. Immunotherapies such as immune checkpoint inhibitors (ICIs) derive their efficacy from this cancer-immune cell interface, however, immune-related adverse events resulting from systemic blockade remain a significant challenge. To address this need for potent, yet highly tumor-specific immunotherapies, we developed Tumor-Immune Cell Targeting Chimeras (TICTACs), antibody conjugates that are capable of selectively depleting immune checkpoint receptors such as SIRPα from the surface of TAMs. These chimeric molecules consist of a synthetic glycan ligand that binds the C-type lectin CD206, a well-established TAM marker, conjugated to a non-blocking antibody that binds but does not inhibit the checkpoint receptor. By engaging CD206, which constitutively recycles between the plasma membrane and early endosomes, TICTACs facilitate robust removal of the checkpoint receptors from the surface of CD206 high macrophages, while having no effect on CD206 low macrophages. By decoupling antibody selectivity from its blocking function, we present a new paradigm for developing highly tumor-specific immunotherapies.
  25. J Hematol Oncol. 2023 Dec 16. 16(1): 121
      Brain metastases signify a deleterious milestone in the progression of several advanced cancers, predominantly originating from lung, breast and melanoma malignancies, with a median survival timeframe nearing six months. Existing therapeutic regimens yield suboptimal outcomes; however, burgeoning insights into the tumor microenvironment, particularly the immunosuppressive milieu engendered by tumor-brain interplay, posit immunotherapy as a promising avenue for ameliorating brain metastases. In this review, we meticulously delineate the research advancements concerning the microenvironment of brain metastases, striving to elucidate the panorama of their onset and evolution. We encapsulate three emergent immunotherapeutic strategies, namely immune checkpoint inhibition, chimeric antigen receptor (CAR) T cell transplantation and glial cell-targeted immunoenhancement. We underscore the imperative of aligning immunotherapy development with in-depth understanding of the tumor microenvironment and engendering innovative delivery platforms. Moreover, the integration with established or avant-garde physical methodologies and localized applications warrants consideration in the prevailing therapeutic schema.
    Keywords:  Brain metastases; CAR-T cells; Glial cells; Immune checkpoint inhibitors; Immunotherapy; Tumor microenvironment
  26. Small. 2023 Dec 15. e2307390
      Tumor immunotherapy has become a research hotspot in cancer treatment, with macrophages playing a crucial role in tumor development. However, the tumor microenvironment restricts macrophage functionality, limiting their therapeutic potential. Therefore, modulating macrophage function and polarization is essential for enhancing tumor immunotherapy outcomes. Here, a supramolecular peptide amphiphile drug-delivery system (SPADS) is utilized to reprogram macrophages and reshape the tumor immune microenvironment (TIM) for immune-based therapies. The approach involved designing highly specific SPADS that selectively targets surface receptors of M2-type macrophages (M2-Mφ). These targeted peptides induced M2-Mφ repolarization into M1-type macrophages by dual inhibition of endoplasmic reticulum and oxidative stresses, resulting in improved macrophagic antitumor activity and immunoregulatory function. Additionally, TIM reshaping disrupted the immune evasion mechanisms employed by tumor cells, leading to increased infiltration, and activation of immune cells. Furthermore, the synergistic effect of macrophage reshaping and anti-PD-1 antibody (aPD-1) therapy significantly improved the immune system's ability to recognize and eliminate tumor cells, thereby enhancing tumor immunotherapy efficacy. SPADS utilization also induced lung metastasis suppression. Overall, this study demonstrates the potential of SPADS to drive macrophage reprogramming and reshape TIM, providing new insights, and directions for developing more effective immunotherapeutic approaches in cancer treatment.
    Keywords:  immune microenvironment; macrophage repolarization; peptide self-assembly; targeting delivery; tumor immunotherapy
  27. Cells. 2023 Dec 08. pii: 2801. [Epub ahead of print]12(24):
      In recent years, there has been a growing interest in the relationship between microorganisms in the surrounding environment and cancer cells. While the tumor microenvironment predominantly comprises cancer cells, stromal cells, and immune cells, emerging research highlights the significant contributions of microbial cells to tumor development and progression. Although the impact of the gut microbiome on treatment response in lung cancer is well established, recent investigations indicate complex roles of lung microbiota in lung cancer. This article focuses on recent findings on the human lung microbiome and its impacts in cancer development and progression. We delve into the characteristics of the lung microbiome and its influence on lung cancer development. Additionally, we explore the characteristics of the intratumoral microbiome, the metabolic interactions between lung tumor cells, and how microorganism-produced metabolites can contribute to cancer progression. Furthermore, we provide a comprehensive review of the current literature on the lung microbiome and its implications for the metastatic potential of tumor cells. Additionally, this review discusses the potential for therapeutic modulation of the microbiome to establish lung cancer prevention strategies and optimize lung cancer treatment.
    Keywords:  immunotherapy; lung cancer; microbiome; tumor microenvironment (TME)
  28. Cancers (Basel). 2023 Dec 15. pii: 5857. [Epub ahead of print]15(24):
      Cancer immunotherapy has ushered in a transformative era in oncology, offering unprecedented promise and opportunities. Despite its remarkable breakthroughs, the field continues to grapple with the persistent challenge of treatment resistance. This resistance not only undermines the widespread efficacy of these pioneering treatments, but also underscores the pressing need for further research. Our exploration into the intricate realm of cancer immunotherapy resistance reveals various mechanisms at play, from primary and secondary resistance to the significant impact of genetic and epigenetic factors, as well as the crucial role of the tumor microenvironment (TME). Furthermore, we stress the importance of devising innovative strategies to counteract this resistance, such as employing combination therapies, tailoring immune checkpoints, and implementing real-time monitoring. By championing these state-of-the-art methods, we anticipate a paradigm that blends personalized healthcare with improved treatment options and is firmly committed to patient welfare. Through a comprehensive and multifaceted approach, we strive to tackle the challenges of resistance, aspiring to elevate cancer immunotherapy as a beacon of hope for patients around the world.
    Keywords:  adoptive cell therapies; cancer immunotherapy; cancer vaccines; combination therapies; immune checkpoint targets; personalized medicine; resistance; tumor microenvironment
  29. Biomed Pharmacother. 2023 Dec 20. pii: S0753-3322(23)01828-0. [Epub ahead of print]170 116030
      Gastric cancer (GC) is a malignant tumor of the gastrointestinal tract with a high mortality rate worldwide, a low early detection rate and a poor prognosis. The rise of metabolomics has facilitated the early detection and treatment of GC. Metabolism in the GC tumor microenvironment (TME) mainly includes glucose metabolism, lipid metabolism and amino acid metabolism, which provide energy and nutrients for GC cell proliferation and migration. Abnormal tumor metabolism can influence tumor progression by regulating the functions of immune cells and immune molecules in the TME, thereby contributing to tumor immune escape. Thus, in this review, we summarize the impact of metabolism on the TME during GC progression. We also propose novel strategies to modulate antitumor immune responses by targeting metabolism.
    Keywords:  Cancer immunity; Gastric cancer; Immune microenvironment; Metabolism; TIME
  30. Cancer Res. 2023 Dec 20.
      Adipose tissue within the tumor microenvironment (TME) plays a critical role in supporting breast cancer progression. In this study, we identified FAM3 metabolism-regulating signaling molecule C (FAM3C) produced by cancer-associated adipocytes (CAAs) as a key regulator of tumor progression. FAM3C overexpression in cultured adipocytes significantly reduced cell death in both adipocytes and co-cultured breast cancer cells while suppressing markers of fibrosis. Conversely, FAM3C depletion in CAAs resulted in adipocyte-mesenchymal transition (AMT) and increased fibrosis within the TME. Adipocyte FAM3C expression was driven by TGF-β signaling from breast cancer cells and was reduced upon treatment with a TGF-β-neutralizing antibody. FAM3C knockdown in CAAs early in tumorigenesis in a genetically engineered mouse model of breast cancer significantly inhibited primary and metastatic tumor growth. Circulating FAM3C levels were elevated in patients with metastatic breast cancer compared to those with non-metastatic breast cancer. These results suggest that therapeutic inhibition of FAM3C expression levels in CAAs during early tumor development could be a promising approach in the treatment of patients with breast cancer.
  31. Phys Rev E. 2023 Nov;108(5-1): 054105
      Normal life activities between cells rely crucially on the homeostasis of the cellular microenvironment, but aging and cancer will upset this balance. In this paper we introduce the microenvironmental feedback mechanism to the growth dynamics of multicellular organisms, which changes the cellular competitive ability and thereby regulates the growth of multicellular organisms. We show that the presence of microenvironmental feedback can effectively delay aging, but cancer cells may grow uncontrollably due to the emergence of the tumor microenvironment (TME). We study the effect of the fraction of cancer cells relative to that of senescent cells on the feedback rate of the microenvironment on the lifespan of multicellular organisms and find that the average lifespan shortened is close to the data for non-Hodgkin's lymphoma in Canada from 1980 to 2015. We also investigate how the competitive ability of cancer cells affects the lifespan of multicellular organisms and reveal that there is an optimal value of the competitive ability of cancer cells allowing the organism to survive longest. Interestingly, the proposed microenvironmental feedback mechanism can give rise to the phenomenon of Parrondo's paradox: When the competitive ability of cancer cells switches between a too-high and a too-low value, multicellular organisms are able to live longer than in each case individually. Our results may provide helpful clues for targeted therapies aimed at the TME.
  32. Biomed Pharmacother. 2023 Dec 18. pii: S0753-3322(23)01838-3. [Epub ahead of print]170 116040
      Colorectal cancer is a common malignancy with significant rates of morbidity and mortality. A number of factors, including the tumor microenvironment, chemokines, the inflammatory response, have an impact on the development of colorectal cancer. A critical component of the tumor microenvironment is chemokines. Various cell subsets are attracted to the tumor microenvironment through interactions with chemokine receptors. These cells have varying effects on the development of the tumor and the effectiveness of treatment. Additionally, chemokines can participate in inflammatory processes and have effects that are either pro- or anti-tumor. Chemokines can be exploited as targets for medication resistance and treatment in colorectal cancer. In this review, we discuss the expression of chemokines and chemokine receptors, and their relationship with immune cells in the tumor microenvironment. At the same time, we also collect and discuss the significance of chemokines and chemokine receptors in colorectal cancer progression, and their potential as molecular targets for CRC treatment.
    Keywords:  Chemokines; Chemokines receptors; Colorectal cancer; Inflammation; Tumor microenvironment
  33. Cancers (Basel). 2023 Dec 15. pii: 5852. [Epub ahead of print]15(24):
      Chimeric antigen receptor (CAR) cell-based therapies have demonstrated limited success in solid tumors, including glioblastoma (GBM). GBMs exhibit high heterogeneity and create an immunosuppressive tumor microenvironment (TME). In addition, other challenges exist for CAR therapy, including trafficking and infiltration into the tumor site, proliferation, persistence of CARs once in the tumor, and reduced functionality, such as suboptimal cytokine production. Cytokine modification is of interest, as one can enhance therapy efficacy and minimize off-target toxicity by directly combining CAR therapy with cytokines, antibodies, or oncolytic viruses that alter cytokine response pathways. Alternatively, one can genetically modify CAR T-cells or CAR NK-cells to secrete cytokines or express cytokines or cytokine receptors. Finally, CARs can be genetically altered to augment or suppress intracellular cytokine signaling pathways for a more direct approach. Codelivery of cytokines with CARs is the most straightforward method, but it has associated toxicity. Alternatively, combining CAR therapy with antibodies (e.g., anti-IL-6, anti-PD1, and anti-VEGF) or oncolytic viruses has enhanced CAR cell infiltration into GBM tumors and provided proinflammatory signals to the TME. CAR T- or NK-cells secreting cytokines (e.g., IL-12, IL-15, and IL-18) have shown improved efficacy within multiple GBM subtypes. Likewise, expressing cytokine-modulating receptors in CAR cells that promote or inhibit cytokine signaling has enhanced their activity. Finally, gene editing approaches are actively being pursued to directly influence immune signaling pathways in CAR cells. In this review, we summarize these cytokine modification methods and highlight any existing gaps in the hope of catalyzing an improved generation of CAR-based therapies for glioblastoma.
    Keywords:  CAR NK-cell; CAR T-cell; chemokine; cytokine; glioblastoma
  34. Cancers (Basel). 2023 Dec 08. pii: 5760. [Epub ahead of print]15(24):
      Soft tissue sarcomas (STSs) are a rare heterogeneous group of malignant neoplasms characterized by their aggressive course and poor response to treatment. This determines the relevance of research aimed at studying the pathogenesis of STSs. By now, it is known that STSs is characterized by complex relationships between the tumor cells and immune cells of the microenvironment. Dynamic interactions between tumor cells and components of the microenvironment enhance adaptation to changing environmental conditions, which provides the high aggressive potential of STSs and resistance to antitumor therapy. Today, active research is being conducted to find effective antitumor drugs and to evaluate the possibility of using therapy with immune cells of STS. The difficulty in assessing the efficacy of new antitumor options is primarily due to the high heterogeneity of this group of malignant neoplasms. Studying the role of immune cells in the microenvironment in the progression STSs and resistance to antitumor therapies will provide the discovery of new biomarkers of the disease and the prediction of response to immunotherapy. In addition, it will help to initially divide patients into subgroups of good and poor response to immunotherapy, thus avoiding wasting precious time in selecting the appropriate antitumor agent.
    Keywords:  antitumor agents; immune cells; immunotherapy; soft tissue sarcoma; tumor microenvironment; tumor-associated macrophages; tumor-infiltrating lymphocytes
  35. Cancers (Basel). 2023 Dec 08. pii: 5765. [Epub ahead of print]15(24):
      CAR-T cell therapy has revolutionized the treatment of hematological malignancies with high remission rates in the case of ALL and NHL. This therapy has some limitations such as long manufacturing periods, persistent restricted cell sources and high costs. Moreover, combination regimens increase the risk of immune-related adverse events, so the identification new therapeutic targets is important to minimize the risk of toxicities and to guide more effective approaches. Cancer cells employ several mechanisms to evade immunosurveillance, which causes resistance to immunotherapy; therefore, a very important therapeutic approach is to focus on the development of rational combinations of targeted therapies with non-overlapping toxicities. Recent progress in the development of new inhibitory clusters of differentiation (CDs), signaling pathway molecules, checkpoint inhibitors, and immunosuppressive cell subsets and factors in the tumor microenvironment (TME) has significantly improved anticancer responses. Novel strategies regarding combination immunotherapies with CAR-T cells are the most promising approach to cure cancer.
    Keywords:  CR-T; TME; checkpoint inhibitors; hematological malignancies; immunotherapy