bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2024‒04‒14
forty-four papers selected by
Peio Azcoaga, Biodonostia HRI

  1. MedComm (2020). 2024 Apr;5(4): e541
      Exosomes are indispensable for intercellular communications. Tumor microenvironment (TME) is the living environment of tumor cells, which is composed of various components, including immune cells. Based on TME, immunotherapy has been recently developed for eradicating cancer cells by reactivating antitumor effect of immune cells. The communications between tumor cells and TME are crucial for tumor development, metastasis, and drug resistance. Exosomes play an important role in mediating these communications and regulating the reprogramming of TME, which affects the sensitivity of immunotherapy. Therefore, it is imperative to investigate the role of exosomes in TME reprogramming and the impact of exosomes on immunotherapy. Here, we review the communication role of exosomes in regulating TME remodeling and the efficacy of immunotherapy, as well as summarize the underlying mechanisms. Furthermore, we also introduce the potential application of the artificially modified exosomes as the delivery systems of antitumor drugs. Further efforts in this field will provide new insights on the roles of exosomes in intercellular communications of TME and cancer progression, thus helping us to uncover effective strategies for cancer treatment.
    Keywords:  exosomes; immunotherapy; intercellular communications; tumor microenvironment; tumor therapy
  2. Int J Mol Sci. 2024 Mar 25. pii: 3642. [Epub ahead of print]25(7):
      The tumor microenvironment (TME) plays a critical role in cancerogenesis [...].
  3. Curr Drug Deliv. 2024 Apr 08.
      Macrophages are immune cells with high heterogeneity and plasticity, crucial for recognizing and eliminating foreign substances, including cancer cells. However, cancer cells can evade the immune system by producing signals that cause macrophages to switch to a pro-tumor phenotype, promoting tumor growth and progression. Tumor-associated macrophages, which infiltrate into tumor tissue, are important immune cells in the tumor microenvironment and can regulate cancer's growth, invasion, and metastasis by inhibiting tumor immunity. This review article highlights the characteristics of tumor-associated macrophages and their role in the occurrence and development of cancer. It outlines how reprogramming macrophages towards an anti-tumor phenotype can improve the response to cancer therapy. Explore the intricate process of engineered nanoparticles serving as carriers for immunostimulatory molecules, activating macrophages to instigate an anti-tumor response. Finally, it summarizes several studies demonstrating targeting macrophages is a potential in preclinical cancer models. Several challenges must be addressed in developing effective macrophage-targeted therapies, such as the heterogeneity of macrophage subtypes and their plasticity. Further research is needed to understand the mechanisms underlying macrophage function in the tumor microenvironment and identify novel targets for macrophage-directed therapies. Targeting macrophages is a promising and innovative approach to improving cancer therapy and patient outcomes.
    Keywords:  Tumor-associated macrophages; immunotherapy; innate and adaptive immunity; nanomedicine.; tumor microenvironment; tumor- associated antigens
  4. Front Immunol. 2024 ;15 1381225
      Macrophages are the main component of the tumor microenvironment, which are differentiated from monocytes in the blood and play an important role in cancer development. Tumor-associated macrophages (TAMs) can promote tumor growth, invasion, metastasis, and resistance to anti-programmed death receptor 1 therapy by regulating programmed cell death ligand 1 expression and interacting with other immune cells in the tumor microenvironment. However, when activated properly, macrophages can also play an anti-tumor role by enhancing the phagocytosis and cytotoxicity of tumor cells. TAM is associated with poor prognosis and drug resistance in patients treated with immunotherapy, indicating that macrophages are attractive targets for combined therapy in cancer treatment. Combination of targeting TAMs and immunotherapy overcomes the drug resistance and achieved excellent results in some cancers, which may be a promising strategy for cancer treatment in the future. Herein, we review the recent findings on the role of macrophages in tumor development, metastasis, and immunotherapy. We focus mainly on macrophage≥centered therapy, including strategies to deplete and reprogram TAMs, which represent the potential targets for improving tumor immunotherapy efficacy.
    Keywords:  PD-L1; cancer; immunotherapy; macrophages; tumor microenvironment
  5. J Physiol Biochem. 2024 Apr 08.
      Fasting and fasting-mimicking conditions modulate tumor metabolism and remodel the tumor microenvironment (TME), which could be exploited for the treatment of tumors. A body of evidence demonstrates that fasting and fasting-mimicking conditions can kill cancer cells, or sensitize them to the antitumor activity of standard-of-care drugs while protecting normal cells against their toxic side effects. Pre- and clinical data also suggest that immune responses are involved in these therapeutic effects. Therefore, there is increasing interest in evaluating the impact of fasting-like conditions in the efficacy of antitumor therapies based on the restoration or activation of antitumor immune responses. Here, we review the recent progress in the intersection of fasting-like conditions and current cancer treatments, with an emphasis on cancer immunotherapy.
    Keywords:  Cancer immunotherapy; Cancer treatment toxic side effects; Fasting; Fasting-mimicking conditions; Tumor immunity
  6. J Mol Med (Berl). 2024 Apr 11.
      The accumulation of senescent cells within tissues is a hallmark of the aging process. Senescent cells are also commonly present in many age-related diseases and in the cancer microenvironment. The escape of abnormal cells from immune surveillance indicates that there is some defect in the function of cytotoxic immune cells, e.g., CD8+ T cells and natural killer (NK) cells. Recent studies have revealed that the expression of programmed death-ligand 1 (PD-L1) protein is abundantly increased in senescent cells. An increase in the amount of PD-L1 protein protects senescent cells from clearance by the PD-1 checkpoint receptor in cytotoxic immune cells. In fact, the activation of the PD-1 receptor suppresses the cytotoxic properties of CD8+ T and NK cells, promoting a state of immunosenescence. The inhibitory PD-1/PD-L1 checkpoint pathway acts in cooperation with immunosuppressive cells; for example, activation of PD-1 receptor can enhance the differentiation of regulatory T cells (Treg), myeloid-derived suppressor cells (MDSC), and M2 macrophages, whereas the cytokines secreted by immunosuppressive cells stimulate the expression of the immunosuppressive PD-L1 protein. Interestingly, many signaling pathways known to promote cellular senescence and the aging process are crucial stimulators of the expression of PD-L1 protein, e.g., epigenetic regulation, inflammatory mediators, mTOR-related signaling, cGAS-STING pathway, and AhR signaling. It seems that the inhibitory PD-1/PD-L1 immune checkpoint axis has a crucial role in the accumulation of senescent cells and thus it promotes the aging process in tissues. Thus, the blockade of the PD-1/PD-L1 checkpoint signaling might be a potential anti-aging senolytic therapy. KEY MESSAGES: Senescent cells accumulate within tissues during aging and age-related diseases. Senescent cells are able to escape immune surveillance by cytotoxic immune cells. Expression of programmed death-ligand 1 (PD-L1) markedly increases in senescent cells. Age-related signaling stimulates the expression of PD-L1 protein in senescent cells. Inhibitory PD-1/PD-L1 checkpoint pathway suppresses clearance of senescent cells.
    Keywords:  Aging; Immune tolerance; Immunosuppression; Inflammaging; Inflammation
  7. Cytokine. 2024 Apr 05. pii: S1043-4666(24)00093-0. [Epub ahead of print]179 156590
      BACKGROUND: The tumor microenvironment (TME) and interleukin-22 (IL-22) in cytokines have recently attracted much attention due to their potential impact on tumor biology. However, the role of IL-22 in triple negative breast cancer (TNBC) TME is still poorly understood. This article investigated the gene expression and function of IL-22 in TNBC TME.METHODS: Tumor samples from TNBC patients were collected, and adjacent noncancerous tissues were used as controls. A functional test was performed to evaluate the impact of IL-22 for TNBC cells, including proliferation, migration, and apoptosis.
    RESULTS: IL-22 gene expression in TNBC tumor samples was markedly higher relative to adjacent non-cancerous tissues (P < 0.05). In addition, it was also observed that IL-22facilitated proliferation and migration of TNBC cells, and inhibit apoptosis. This article reveals the role of IL-22 in the TME of TNBC. The up-regulation of IL-22 gene expression in TNBC tumors and its promoting effect on cancer cell invasiveness highlight its potential as a therapeutic target in TNBC treatment strategies.
    CONCLUSION: The findings suggested that targeting IL-22 and its related pathways can offer new insights for developing effective therapies for TNBC.
    Keywords:  Function of cells; Gene expression; IL-22; TME; TNBC
  8. Biochim Biophys Acta Mol Basis Dis. 2024 Apr 08. pii: S0925-4439(24)00153-4. [Epub ahead of print] 167164
      Cancer stem cells (CSCs) are a subset of tumor cells that can initiate and sustain tumor growth and cause recurrence and metastasis. CSCs are particularly resistant to conventional therapies compared to their counterparts, owing greatly to their intrinsic metabolic plasticity. Metabolic plasticity allows CSCs to switch between different energy production and usage pathways based on environmental and extrinsic factors, including conditions imposed by conventional cancer therapies. To cope with nutrient deprivation and therapeutic stress, CSCs can transpose between glycolysis and oxidative phosphorylation (OXPHOS) metabolism. The mechanism behind the metabolic pathway switch in CSCs is not fully understood, however, some evidence suggests that the tumor microenvironment (TME) may play an influential role mediated by its release of signals, such as Wnt/β-catenin and Notch pathways, as well as a background of hypoxia. Exploring the factors that promote metabolic plasticity in CSCs offers the possibility of eventually developing therapies that may more effectively eliminate the crucial tumor cell subtype and alter the disease course substantially.
    Keywords:  Cancer stem cells; Glycolysis; Metabolic plasticity; Metastasis; Oxidative phosphorylation; Recurrence; Tumor microenvironment
  9. Clin Transl Oncol. 2024 Apr 11.
      The journey of cancer development is a multifaceted and staged process. The array of treatments available for cancer varies significantly, dictated by the disease's type and stage. Cancer-associated fibroblasts (CAFs), prevalent across various cancer types and stages, play a pivotal role in tumor genesis, progression, metastasis, and drug resistance. The strategy of concurrently targeting cancer cells and CAFs holds great promise in cancer therapy. In this review, we focus intently on CAFs, delving into their critical role in cancer's progression. We begin by exploring the origins, classification, and surface markers of CAFs. Following this, we emphasize the key cytokines and signaling pathways involved in the interplay between cancer cells and CAFs and their influence on the tumor immune microenvironment. Additionally, we examine current therapeutic approaches targeting CAFs. This article underscores the multifarious roles of CAFs within the tumor microenvironment and their potential applications in cancer treatment, highlighting their importance as key targets in overcoming drug resistance and enhancing the efficacy of tumor therapies.
    Keywords:  Cancer treatment; Cancer-associated fibroblasts; Drug resistance; Tumor immune microenvironment; Tumor microenvironment
  10. Exp Hematol Oncol. 2024 Apr 12. 13(1): 39
      Paradoxically, tumor development and progression can be inhibited and promoted by the immune system. After three stages of immune editing, namely, elimination, homeostasis and escape, tumor cells are no longer restricted by immune surveillance and thus develop into clinical tumors. The mechanisms of immune escape include abnormalities in antitumor-associated immune cells, selection for immune resistance to tumor cells, impaired transport of T cells, and the formation of an immunosuppressive tumor microenvironment. A population of distinct immature myeloid cells, myeloid-derived suppressor cells (MDSCs), mediate immune escape primarily by exerting immunosuppressive effects and participating in the constitution of an immunosuppressive microtumor environment. Clinical trials have found that the levels of MDSCs in the peripheral blood of cancer patients are strongly correlated with tumor stage, metastasis and prognosis. Moreover, animal experiments have confirmed that elimination of MDSCs inhibits tumor growth and metastasis to some extent. Therefore, MDSCs may become the target of immunotherapy for many cancers, and eliminating MDSCs can help improve the response rate to cancer treatment and patient survival. However, a clear definition of MDSCs and the specific mechanism involved in immune escape are lacking. In this paper, we review the role of the MDSCs population in tumor development and the mechanisms involved in immune escape in different tumor contexts. In addition, we discuss the use of these cells as targets for tumor immunotherapy. This review not only contributes to a systematic and comprehensive understanding of the essential role of MDSCs in immune system reactions against tumors but also provides information to guide the development of cancer therapies targeting MDSCs.
    Keywords:  Immune escape; Myeloid-derived suppressor cells; Targeting therapy; Tumor immunology
  11. bioRxiv. 2024 Mar 26. pii: 2024.03.21.586041. [Epub ahead of print]
      Macrophages are pivotal in driving breast tumor development, progression, and resistance to treatment, particularly in estrogen receptor-positive (ER+) tumors, where they infiltrate the tumor microenvironment (TME) influenced by cancer cell-secreted factors. By analyzing single-cell RNA-sequencing data from 25 ER+ tumors, we elucidated interactions between cancer cells and macrophages, correlating macrophage density with epithelial cancer cell density. We identified that S100A11, a previously unexplored factor in macrophage-cancer crosstalk, predicts high macrophage density and poor outcomes in ER+ tumors. We found that recombinant S100A11 enhances macrophage infiltration and migration in a dose-dependent manner. Additionally, in 3D models, we showed that S100A11 expression levels in ER+ cancer cells predict macrophage infiltration patterns. Neutralizing S100A11 decreased macrophage recruitment, both in cancer cell lines and in a clinically relevant patient-derived organoid model, underscoring its role as a paracrine regulator of cancer-macrophage interactions in the pro-tumorigenic TME. This study offers novel insights into the interplay between macrophages and cancer cells in ER+ breast tumors, highlighting S100A11 as a potential therapeutic target to modulate the macrophage-rich tumor microenvironment.
  12. Cancer Metastasis Rev. 2024 Apr 11.
      Tumor microenvironment (TME) has been demonstrated to play a significant role in tumor initiation, progression, and metastasis. Cancer-associated fibroblasts (CAFs) are the major component of TME and exhibit heterogeneous properties in their communication with tumor cells. This heterogeneity of CAFs can be attributed to various origins, including quiescent fibroblasts, mesenchymal stem cells (MSCs), adipocytes, pericytes, endothelial cells, and mesothelial cells. Moreover, single-cell RNA sequencing has identified diverse phenotypes of CAFs, with myofibroblastic CAFs (myCAFs) and inflammatory CAFs (iCAFs) being the most acknowledged, alongside newly discovered subtypes like antigen-presenting CAFs (apCAFs). Due to these heterogeneities, CAFs exert multiple functions in tumorigenesis, cancer stemness, angiogenesis, immunosuppression, metabolism, and metastasis. As a result, targeted therapies aimed at the TME, particularly focusing on CAFs, are rapidly developing, fueling the promising future of advanced tumor-targeted therapy.
    Keywords:  EMT; Molecular marker; TGF-β; Tumor microenvironment
  13. MedComm (2020). 2024 Apr;5(4): e528
      Lipid metabolic reprogramming is closely related to tumor progression with the mechanism not fully elucidated. Here, we report the immune-regulated role of lanosterol synthase (LSS), an essential enzyme in cholesterol synthesis. Database analysis and clinical sample experiments suggest that LSS was lowly expressed in colon and breast cancer tissues, which indicates poor prognosis. The biological activity of tumor cell lines and tumor progression in NOD scid gamma (NSG) mice were not affected after LSS knockdown, whereas LSS deficiency obviously aggravated tumor burden in fully immunized mice. Flow cytometry analysis showed that LSS knockdown significantly promoted the formation of tumor immunosuppressive microenvironment, characterized by the increase in M2 macrophages and polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), as well as the decrease in anti-tumoral T lymphocytes. With the inhibition of myeloid infiltration or loss function of T lymphocytes, the propulsive effect of LSS knockdown on tumor progression disappeared. Mechanistically, LSS knockdown increased programmed death ligand 1 (PDL1) protein stability by 2,3-oxidosqualene (OS) binding to PDL1 protein. Anti-PDL1 therapy abolished LSS deficiency-induced immunosuppressive microenvironment and cancer progression. In conclusion, our results show that LSS deficiency promotes tumor progression by establishing an OS-PDL1 axis-dependent immunosuppressive microenvironment, indicative of LSS or OS as a potential hallmark of response to immune checkpoint blockade.
    Keywords:  lanosterol synthase; programmed cell death ligand 1; tumor immunity; tumor microenvironment
  14. Trends Cancer. 2024 Apr 09. pii: S2405-8033(24)00057-8. [Epub ahead of print]
      Although immunotherapy has revolutionized solid tumor treatment, durable responses in gastric cancer (GC) remain limited. The heterogeneous tumor microenvironment (TME) facilitates immune evasion, contributing to resistance to conventional and immune therapies. Recent studies have highlighted how specific TME components in GC acquire immune escape capabilities through cancer-specific factors. Understanding the underlying molecular mechanisms and targeting the immunosuppressive TME will enhance immunotherapy efficacy and patient outcomes. This review summarizes recent advances in GC TME research and explores the role of the immune-suppressive system as a context-specific determinant. We also provide insights into potential treatments beyond checkpoint inhibition.
    Keywords:  TME-based clinical trial; gastric cancer; peritoneal metastasis; single-cell analysis
  15. Sci Rep. 2024 04 08. 14(1): 8179
      Breast cancer has been reported to correlate with the infiltration of tumor-associated macrophages (TAMs) or M2-like macrophages in tumor microenvironment (TME) that could promote breast cancer progression. In contrast, M1-like macrophages displayed anti-tumor activity toward cancer. This study was focused on Auricularia polytricha (AP), a cloud ear mushroom, which has been reported for anti-tumor activity and immunomodulation. AP extracts were screened on differentiated THP-1 macrophages (M0). Results demonstrated that water extract (APW) and crude polysaccharides (APW-CP) could upregulate M1-related genes and cytokines production (IL-6, IL-1 β and TNF-α) significantly. Moreover, APW and APW-CP showed a high expression of CD86 (M1 marker) compared to M0. The NF-κB signaling pathway is crucial for pro-inflammatory gene regulation. The APW and APW-CP treatment showed the induction of the NF-κB pathway in a dose-dependent manner, which related to the β-glucan content in the extracts. Furthermore, APW-CP polarized macrophages were investigated for anti-tumor activity on human breast cancer cells (MCF-7 and MDA-MB-231). Results showed that APW-CP could inhibit the invasion of breast cancer cells and induce apoptosis. Therefore, M1 macrophages polarized by APW-CP showed anti-tumor activity against the breast cancer cells and β-glucan may be the potential M1-phenotype inducer.
  16. Int J Mol Sci. 2024 Apr 02. pii: 3950. [Epub ahead of print]25(7):
      IL-1α is a dual function cytokine that affects inflammatory and immune responses and plays a pivotal role in cancer. The effects of intracellular IL-1α on the development of triple negative breast cancer (TNBC) in mice were assessed using the CRISPR/Cas9 system to suppress IL-1α expression in 4T1 breast cancer cells. Knockout of IL-1α in 4T1 cells modified expression of multiple genes, including downregulation of cytokines and chemokines involved in the recruitment of tumor-associated pro-inflammatory cells. Orthotopical injection of IL-1α knockout (KO) 4T1 cells into BALB/c mice led to a significant decrease in local tumor growth and lung metastases, compared to injection of wild-type 4T1 (4T1/WT) cells. Neutrophils and myeloid-derived suppressor cells were abundant in tumors developing after injection of 4T1/WT cells, whereas more antigen-presenting cells were observed in the tumor microenvironment after injection of IL-1α KO 4T1 cells. This switch correlated with increased infiltration of CD3+CD8+ and NKp46+cells. Engraftment of IL-1α knockout 4T1 cells into immunodeficient NOD.SCID mice resulted in more rapid tumor growth, with increased lung metastasis in comparison to engraftment of 4T1/WT cells. Our results suggest that tumor-associated IL-1α is involved in TNBC progression in mice by modulating the interplay between immunosuppressive pro-inflammatory cells vs. antigen-presenting and cytotoxic cells.
    Keywords:  MDSC; inflammation; interleukin-1-alpha; intracellular IL-1α; metastasis
  17. Immunity. 2024 Apr 09. pii: S1074-7613(24)00134-1. [Epub ahead of print]57(4): 840-842
      Stress hormones can contribute to cancer progression, but how immune cells play a role in this process is unclear. In a recent study in Cancer Cell, He et al. showed that glucocorticoids potentiate metastasis by skewing neutrophils toward pro-tumorigenic functions.
  18. Int Immunopharmacol. 2024 Apr 09. pii: S1567-5769(24)00553-8. [Epub ahead of print]132 112035
      Hallmark features of the tumor microenvironment include immune cells, stromal cells, blood vessels, and extracellular matrix (ECM), providing a conducive environment for the growth and survival of tumors. Recent advances in the understanding of cancer biology have highlighted the functional role of semaphorins (SEMAs). SEMAs are a large and diverse family of widely expressed secreted and membrane-binding proteins, which were initially implicated in axon guidance and neural development. However, it is now clear that they are widely expressed beyond the nervous system and participate in regulating immune responses and cancer progression. In fact, accumulating evidence disclosed that different SEMAs can either stimulate or restrict tumor progression, some of which act as important regulators of tumor angiogenesis. Conversely, limited information is known about the functional relevance of SEMA signals in TME. In this setting, we systematically elaborate the role SEMAs and their major receptors played in characterized components of TME. Furthermore, we provide a convergent view of current SEMAs pharmacological progress in clinical treatment and also put forward their potential application value and clinical prospects in the future.
    Keywords:  Biological mechanisms; Semaphorins; Therapeutic progress; Tumor microenvironment
  19. J Nutr Biochem. 2024 Apr 09. pii: S0955-2863(24)00080-9. [Epub ahead of print] 109647
      Macrophages are phagocytic cells with important physiological functions, including the digestion of cellular debris, foreign substances, and microbes, as well as tissue development and homeostasis. The tumor microenvironment (TME) shapes the aggressiveness of cancer, and the biological and cellular interactions in this complicated space can determine carcinogenesis. The TME can determine the progression, biological behavior, and therapy resistance of human cancers. The macrophages are among the most abundant cells in the TME, and their functions and secretions can determine tumor progression. The education of macrophages to M2 polarization can accelerate cancer progression, and therefore, the re-education and reprogramming of these cells is promising. Moreover, macrophages can cause inflammation in aggravating pathological events, including cardiovascular diseases, diabetes, and neurological disorders. The natural products are pleiotropic and broad-spectrum functional compounds that have been deployed as ideal alternatives to conventional drugs in the treatment of cancer. The biological and cellular interactions in the TME can be regulated by natural products, and for this purpose, they enhance the M1 polarization of macrophages, and in addition to inhibiting proliferation and invasion, they impair the chemoresistance. Moreover, since macrophages and changes in the molecular pathways in these cells can cause inflammation, the natural products impair the pro-inflammatory function of macrophages to prevent the pathogenesis and progression of diseases. Even a reduction in macrophage-mediated inflammation can prevent organ fibrosis. Therefore, natural product-mediated macrophage targeting can alleviate both cancerous and non-cancerous diseases.
    Keywords:  Phytochemicals; cancer; inflammatory diseases; macrophages; tumor microenvironment
  20. Mol Ther. 2024 Apr 06. pii: S1525-0016(24)00221-1. [Epub ahead of print]
      The clinical potential of current FDA-approved chimeric antigen receptor (CAR)-engineered T (CAR-T) cell therapy is encumbered by its autologous nature, which presents notable challenges related to manufacturing complexities, heightened costs, and limitations in patient selection. Therefore, there is a growing demand for off-the-shelf universal cell therapies. In this study, we have generated universal CAR-engineered NKT (UCAR-NKT) cells by integrating iNKT TCR engineering and HLA gene editing on HSCs, along with an ex vivo, feeder-free HSC differentiation culture. The UCAR-NKT cells are produced with high yield, purity, and robustness, and they display a stable HLA-ablated phenotype that enables resistance to host cell-mediated allorejection. These UCAR-NKT cells exhibit potent antitumor efficacy to blood cancers and solid tumors, both in vitro and in vivo, employing a multifaceted array of tumor-targeting mechanisms. These cells are further capable of altering the tumor microenvironment by selectively depleting immunosuppressive tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). Additionally, UCAR-NKT cells demonstrate a favorable safety profile with low risks of graft-versus-host disease (GvHD) and cytokine release syndrome (CRS). Collectively, these preclinical studies underscore the feasibility and significant therapeutic potential of UCAR-NKT cell products and lay a foundation for their translational and clinical development.
  21. Zhongguo Fei Ai Za Zhi. 2024 Mar 20. 27(3): 231-240
      Tumor-associated macrophage (TAM) play a crucial role in the immune microenvironment of lung cancer. Through changes in their phenotype and phagocytic functions, TAM contribute to the initiation and progression of lung cancer. By promoting the formation of an immune-suppressive microenvironment and accelerating the growth of abnormal tumor vasculature, TAM facilitate the invasion and metastasis of lung cancer. Macrophages can polarize into different subtypes with distinct functions and characteristics in response to various stimuli, categorized as anti-tumor M1 and pro-tumor M2 types. In tumor tissues, TAM typically polarize into the alternatively activated M2 phenotype, exhibiting inhibitory effects on tumor immunity. This article reviews the role of anti-angiogenic drugs in modulating TAM phenotypes, highlighting their potential to reprogram M2-type TAM into an anti-tumor M1 phenotype. Additionally, the functional alterations of TAM play a significant role in anti-angiogenic therapy and immunotherapy strategies. In summary, the regulation of TAM polarization and function opens up new avenues for lung cancer treatment and may serve as a novel target for modulating the immune microenvironment of tumors.
    Keywords:  Anti-angiogenic therapy; Lung neoplasms; Polarization; Tumor-associated macrophage
  22. Int J Mol Sci. 2024 Apr 04. pii: 4031. [Epub ahead of print]25(7):
      The tumor microenvironment (TME) plays an essential role in tumor progression and in modulating tumor response to anticancer therapy. Cellular senescence leads to a switch in the cell secretome, characterized by the senescence-associated secretory phenotype (SASP), which may regulate tumorigenesis. Senolytic therapy is considered a novel anticancer strategy that eliminates the deleterious effects of senescent cells in the TME. Here, we show that two different types of senolytic drugs, despite efficiently depleting senescent cells, have opposite effects on cancer-associated fibroblasts (CAFs) and their ability to regulate epithelial-mesenchymal transition (EMT). We found that senolytic drugs, navitoclax and the combination of dasatinib/quercetin, reduced the number of spontaneously senescent and TNF-induced senescent CAFs. Despite the depletion of senescent cells, the combination of dasatinib/quercetin versus navitoclax increased the secretion of the SASP pro-inflammatory cytokine IL-6. This differential effect correlated with the promotion of enhanced migration and EMT in MC38 colorectal cancer cells. Our results demonstrate that some senolytics may have side effects unrelated to their senolytic activity and may promote tumorigenesis. We argue for more careful and extensive studies of the effects of senolytics on various aspects of tumor progression and tumor resistance to therapy before the senolytic strategy is implemented in the clinic.
    Keywords:  cancer-associated fibroblasts (CAFs); colorectal cancer; epithelial–mesenchymal transition (EMT); interleukin-6 (IL-6); senescence; senescence-associated secretory phenotype (SASP)
  23. Molecules. 2024 Mar 26. pii: 1469. [Epub ahead of print]29(7):
      Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, with a high degree of malignancy and poor prognosis. Tumor-associated macrophages (TAMs) have been identified as significant contributors to the growth and metastasis of TNBC through the secretion of various growth factors and chemokines. Salvianolic acid A (SAA) has been shown to have anti-cancer activities. However, the potential activity of SAA on re-polarized TAMs remains unclear. As there is a correlation between the TAMs and TNBC, this study investigates the effect of SAA on TAMs in the TNBC microenvironment. For that purpose, M2 TAM polarization was induced by two kinds of TNBC-conditioned medium (TNBC-TCM) in the absence or presence of SAA. The gene and protein expression of TAM markers were analyzed by qPCR, FCM, IF, ELISA, and Western blot. The protein expression levels of ERK and p-ERK in M2-like TAMs were analyzed by Western blot. The migration and invasion properties of M2-like TAMs were analyzed by Transwell assays. Here, we demonstrated that SAA increased the expression levels of CD86, IL-1β, and iNOS in M2-like TAMs and, conversely, decreased the expression levels of Arg-1 and CD206. Moreover, SAA inhibited the migration and invasion properties of M2-like TAMs effectively and decreased the protein expression of TGF-β1 and p-ERK in a concentration-dependent manner, as well as TGF-β1 gene expression and secretion. Our current findings for the first time demonstrated that SAA inhibits macrophage polarization to M2-like TAMs by inhibiting the ERK pathway and promotes M2-like TAM re-polarization to the M1 TAMs, which may exert its anti-tumor effect by regulating M1/M2 TAM polarization. These findings highlight SAA as a potential regulator of M2 TAMs and the possibility of utilizing SAA to reprogram M2 TAMs offers promising insights for the clinical management of TNBC.
    Keywords:  macrophage polarization; salvianolic acid A; triple-negative breast cancer; tumor-associated macrophage
  24. Heliyon. 2024 Apr 15. 10(7): e28600
      The programmed death-ligand 1 (PD-L1) on the surface of tumor cells binds to the receptor programmed cell death protein 1 (PD-1) on effector T cells, thereby inhibiting the anti-tumor immune response. Immune checkpoint blockade (ICB) therapy targeting PD-1/PD-L1 has been approved for the treatment of human cancers with lasting clinical benefit. However, many cancer patients did not respond to anti-PD-1/PD-L1 antibody blocking therapy or drugs targeting PD-1/PD-L1. Recent studies have shown that the response to PD-1/PD-L1 blockade may be related to the PD-L1 abundance of tumor cells. Therefore, it is of crucial significance to find drugs to regulate the expression of PD-L1, which can provide new strategies to improve the response rate and efficacy of PD-1/PD-L1 blocking in cancer treatment. Here, we found that GABA and baclofen, upregulates the protein level of PD-L1 by reducing the mRNA and protein levels of STUB1, a E3 ubiquitin ligase, thereby decreasing the interaction between STUB1 and PD-L1, and ultimately stabilizing PD-L1. Notably, GABA and baclofen did not affect cell proliferation in vitro, while in the treatment of breast cancer in mice, the therapeutic effect of baclofen combined with anti-PD-L1 antibody is significantly better than that of using anti-PD-L1 antibody alone by stimulating tumor infiltration of CD8+ T cells and antitumor immunity. Taken together, we unveiled a previously unappreciated role of GABA/baclofen in stabilizing PD-L1 and enhancing the immunotherapy of breast cancer.
    Keywords:  Baclofen; GABA; Immunotherapy; PD-L1
  25. Genes Chromosomes Cancer. 2024 Apr;63(4): e23233
      Medulloblastomas, the most common malignant pediatric brain tumors, can be classified into the wingless, sonic hedgehog (SHH), group 3, and group 4 subgroups. Among them, the SHH subgroup with the TP53 mutation and group 3 generally present with the worst patient outcomes due to their high rates of recurrence and metastasis. A novel and effective treatment for refractory medulloblastomas is urgently needed. To date, the tumor microenvironment (TME) has been shown to influence tumor growth, recurrence, and metastasis through immunosuppression, angiogenesis, and chronic inflammation. Treatments targeting TME components have emerged as promising approaches to the treatment of solid tumors. In this review, we summarize progress in research on medulloblastoma microenvironment components and their interactions. We also discuss challenges and future research directions for TME-targeting medulloblastoma therapy.
    Keywords:  extracellular matrix; immune cells; medulloblastoma; tumor microenvironment; tumor‐associated astrocytes; vasculature
  26. Nanomaterials (Basel). 2024 Apr 08. pii: 648. [Epub ahead of print]14(7):
      Nanodynamic therapy (NDT) exerts its anti-tumor effect by activating nanosensitizers to generate large amounts of reactive oxygen species (ROS) in tumor cells. NDT enhances tumor-specific targeting and selectivity by leveraging the tumor microenvironment (TME) and mechanisms that boost anti-tumor immune responses. It also minimizes damage to surrounding healthy tissues and enhances cytotoxicity in tumor cells, showing promise in cancer treatment, with significant potential. This review covers the research progress in five major nanodynamic therapies: photodynamic therapy (PDT), electrodynamic therapy (EDT), sonodynamic therapy (SDT), radiodynamic therapy (RDT), and chemodynamic therapy (CDT), emphasizing the significant role of advanced nanotechnology in the development of NDT for anti-tumor purposes. The mechanisms, effects, and challenges faced by these NDTs are discussed, along with their respective solutions for enhancing anti-tumor efficacy, such as pH response, oxygen delivery, and combined immunotherapy. Finally, this review briefly addresses challenges in the clinical translation of NDT.
    Keywords:  nanodynamic therapy; nanomaterials; reactive oxygen species; tumor therapy
  27. Cancer Discov. 2024 Apr 03. OF1-OF4
      SUMMARY: The recent development of high-dimensional spatial omics tools has revealed the functional importance of the tumor microenvironment in driving tumor progression. Here, we discuss practical factors to consider when designing a spatial biology cohort and offer perspectives on the future of spatial biology research.
  28. Cancer Cell. 2024 Apr 08. pii: S1535-6108(24)00096-5. [Epub ahead of print]42(4): 513-534
      In cancer treatment, the recurrent challenge of inducing apoptosis through conventional therapeutic modalities, often thwarted by therapy resistance, emphasizes the critical need to explore alternative cell death pathways. Ferroptosis, an iron-dependent form of regulated cell death triggered by the lethal accumulation of lipid peroxides on cellular membranes, has emerged as one such promising frontier in oncology. Induction of ferroptosis not only suppresses tumor growth but also holds potential for augmenting immunotherapy responses and surmounting resistance to existing cancer therapies. This review navigates the role of ferroptosis in tumor suppression. Furthermore, we delve into the complex role of ferroptosis within the tumor microenvironment and its interplay with antitumor immunity, offering insights into the prospect of targeting ferroptosis as a strategic approach in cancer therapy.
    Keywords:  cancer therapy; ferroptosis; immunotherapy; therapy resistance; tumor microenvironment; tumor suppression
  29. Aging Dis. 2024 Mar 29.
      Numerous research works have emphasized the critical role that circadian rhythm plays in the tumor microenvironment (TME). The goal of clarifying chrono-pharmacological strategies for improving cancer treatment in clinical settings is a continuous endeavor. Consequently, to enhance the use of time-based pharmaceutical therapies in oncology, combining existing knowledge on circadian rhythms' roles within the TME is essential. This perspective elucidates the functions of circadian rhythms in the TME across various stages of cancer development, progression, and metastasis. Specifically, aging, angiogenesis, and inflammation are implicated in modulating circadian rhythm within the TME. Furthermore, circadian rhythm exerts a profound influence on current cancer treatments and thereby generates chronotheray to manage tumors. From a TME perspective, circadian rhythm offers promising opportunities for cancer prevention and treatment; nevertheless, further study is needed to address unanswered scientific problems.
  30. Trends Mol Med. 2024 Apr 10. pii: S1471-4914(24)00063-7. [Epub ahead of print]
      Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive form of pancreatic cancer, known for its challenging diagnosis and limited treatment options. The focus on metabolic reprogramming as a key factor in tumor initiation, progression, and therapy resistance has gained prominence. In this review we focus on the impact of metabolic changes on the interplay among stromal, immune, and tumor cells, as glutamine and branched-chain amino acids (BCAAs) emerge as pivotal players in modulating immune cell functions and tumor growth. We also discuss ongoing clinical trials that explore metabolic modulation for PDAC, targeting mitochondrial metabolism, asparagine and glutamine addiction, and autophagy inhibition. Overcoming challenges in understanding nutrient effects on immune-stromal-tumor interactions holds promise for innovative therapeutic strategies.
    Keywords:  heterogeneity; immunotherapy; metabolic reprogramming; mitochondrial metabolism; pancreatic cancer; tumor microenvironment
  31. Oncoimmunology. 2024 ;13(1): 2338965
      Immunotherapy has revolutionized the treatment of cancers. Reinvigorating lymphocytes with checkpoint blockade has become a cornerstone of immunotherapy for multiple tumor types, but the treatment of glioblastoma has not yet shown clinical efficacy. A major hurdle to treat GBM with checkpoint blockade is the high degree of myeloid-mediated immunosuppression in brain tumors that limits CD8 T-cell activity. A potential strategy to improve anti-tumor efficacy against glioma is to use myeloid-modulating agents to target immunosuppressive cells, such as myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. We found that the co-inhibition of the chemokine receptors CCR2 and CCR5 in murine model of glioma improves the survival and synergizes robustly with anti-PD-1 therapy. Moreover, the treatment specifically reduced the infiltration of monocytic-MDSCs (M-MDSCs) into brain tumors and increased lymphocyte abundance and cytokine secretion by tumor-infiltrating CD8 T cells. The depletion of T-cell subsets and myeloid cells abrogated the effects of CCR2 and CCR5 blockade, indicating that while broad depletion of myeloid cells does not improve survival, specific reduction in the infiltration of immunosuppressive myeloid cells, such as M-MDSCs, can boost the anti-tumor immune response of lymphocytes. Our study highlights the potential of CCR2/CCR5 co-inhibition in reducing myeloid-mediated immunosuppression in GBM patients.
    Keywords:  Glioma; Immunotherapy; MDSC
  32. Med Oncol. 2024 Apr 09. 41(5): 112
      Despite recent advancements in the diagnosis and treatment of breast cancer (BC), patient outcomes in terms of survival, recurrence, and disease progression remain suboptimal. A significant factor contributing to these challenges is the cellular heterogeneity within BC, particularly the presence of breast cancer stem cells (BCSCs). These cells are thought to serve as the clonogenic nexus for new tumor growth, owing to their hierarchical organization within the tumor. This descriptive review focuses on the evolving strategies to target BCSCs, which have become a pivotal aspect of therapeutic development. We explore a variety of approaches, including targeting specific tumor surface markers (CD133 and CD44), transporters, heat shock proteins, and critical signaling pathways like Notch, Akt, Hedgehog, KLF4, and Wnt/β-catenin. Additionally, we discuss the modulation of the tumor microenvironment through the CXCR-12/CXCR4 axis, manipulation of pH levels, and targeting hypoxia-inducible factors, vascular endothelial growth factor, and CXCR1/2 receptors. Further, this review focuses on the roles of microRNA expression, strategies to induce apoptosis and differentiation in BCSCs, dietary interventions, dendritic cell vaccination, oncolytic viruses, nanotechnology, immunotherapy, and gene therapy. We particularly focused on studies reporting identification of BCSCs, their unique properties and the efficacy of various therapeutic modalities in targeting these cells. By dissecting these approaches, we aim to provide insights into the complex landscape of BC treatment and the potential pathways for improving patient outcomes through targeted BCSC therapies.
    Keywords:  BCSCs; Breast cancer; Chemotherapeutics; Nanocarriers; Signaling pathways; Transporters; Tumor microenvironment; Tumor surface markers
  33. Zhonghua Nan Ke Xue. 2023 Apr;29(4): 353-357
      The relationship between male prostate diseases and the hypoxic microenvironment has drawn increasing attention from the medical world. The role of hypoxia-inducible factor 1 (HIF-1), a typical factor for the hypoxic microenvironment, in prostate diseases is one of the hotspots in recent studies. HIF-1 plays an important role in different prostate diseases by participating in metabolic reprogramming, angiogenesis, tissue remodeling, immune regulation and other life activities. This review focuses on the action mechanisms of HIF-1 in prostatitis, prostatic hyperplasia and prostate cancer.
    Keywords:   hypoxia-inducible factor 1; hypoxic environment; prostatitis; prostatic hyperplasia; prostate cancer
  34. Biomed Pharmacother. 2024 Apr 10. pii: S0753-3322(24)00443-8. [Epub ahead of print]174 116559
      Breast cancer comprises a substantial proportion of cancer diagnoses in women and is a primary cause of cancer-related mortality. While hormone-responsive cases generally have a favorable prognosis, the aggressive nature of triple-negative breast cancer presents challenges, with intrinsic resistance to established treatments being a persistent issue. The complexity intensifies with the emergence of acquired resistance, further complicating the management of breast cancer. Epigenetic changes, encompassing DNA methylation, histone and RNA modifications, and non-coding RNAs, are acknowledged as crucial contributors to the heterogeneity of breast cancer. The unique epigenetic landscape harbored by each cellular component within the tumor microenvironment (TME) adds great diversity to the intricate regulations which influence therapeutic responses. The TME, a sophisticated ecosystem of cellular and non-cellular elements interacting with tumor cells, establishes an immunosuppressive microenvironment and fuels processes such as tumor growth, angiogenesis, and extracellular matrix remodeling. These factors contribute to challenging conditions in cancer treatment by fostering a hypoxic environment, inducing metabolic stress, and creating physical barriers to drug delivery. This article delves into the complex connections between breast cancer treatment response, underlying epigenetic changes, and vital interactions within the TME. To restore sensitivity to treatment, it emphasizes the need for combination therapies considering epigenetic changes specific to individual members of the TME. Recognizing the pivotal role of epigenetics in drug resistance and comprehending the specificities of breast TME is essential for devising more effective therapeutic strategies. The development of reliable biomarkers for patient stratification will facilitate tailored and precise treatment approaches.
    Keywords:  Breast cancer; Drug resistance; Epigenetic regulation; Epigenetic therapy; Immune cells; Tumor microenvironment
  35. Commun Biol. 2024 Apr 09. 7(1): 430
      Despite recent advances in cancer immunotherapy, pancreatic ductal adenocarcinoma (PDAC) remains unresponsive due to an immunosuppressive tumor microenvironment, which is characterized by the abundance of cancer-associated fibroblasts (CAFs). Once identified, CAF-mediated immune inhibitory mechanisms could be exploited for cancer immunotherapy. Siglec receptors are increasingly recognized as immune checkpoints, and their ligands, sialic acids, are known to be overexpressed by cancer cells. Here, we unveil a previously unrecognized role of sialic acid-containing glycans on PDAC CAFs as crucial modulators of myeloid cells. Using multiplex immunohistochemistry and transcriptomics, we show that PDAC stroma is enriched in sialic acid-containing glycans compared to tumor cells and normal fibroblasts, and characterized by ST3GAL4 expression. We demonstrate that sialic acids on CAF cell lines serve as ligands for Siglec-7, -9, -10 and -15, distinct from the ligands on tumor cells, and that these receptors are found on myeloid cells in the stroma of PDAC biopsies. Furthermore, we show that CAFs drive the differentiation of monocytes to immunosuppressive tumor-associated macrophages in vitro, and that CAF sialylation plays a dominant role in this process compared to tumor cell sialylation. Collectively, our findings unravel sialic acids as a mechanism of CAF-mediated immunomodulation, which may provide targets for immunotherapy in PDAC.
  36. Cancer Lett. 2024 Apr 09. pii: S0304-3835(24)00264-7. [Epub ahead of print] 216871
      Chimeric antigen receptor T (CAR-T) cell therapy, as an adoptive immunotherapy, is playing an increasingly important role in the treatment of malignant tumors. CAR-T cells are referred to as "living drugs" as they not only target tumor cells directly, but also induce long-term immune memory that has the potential to provide long-lasting protection. CD19.CAR-T cells have achieved complete response rates of over 90% for acute lymphoblastic leukemia and over 60% for non-Hodgkin's lymphoma. However, the response rate of CAR-T cells in the treatment of solid tumors remains extremely low and the side effects potentially severe. In this review, we discuss the limitations that the solid tumor microenvironment poses for CAR-T application and the solutions that are being developed to address these limitations, in the hope that in the near future, CAR-T therapy for solid tumors can attain the same success rates as are now being seen clinically for hematological malignancies.
    Keywords:  CAR-T; logic gate; solid tumor; tumor microenvironment
  37. Int Immunopharmacol. 2024 Apr 05. pii: S1567-5769(24)00524-1. [Epub ahead of print]132 112006
      This study aimed to investigate the influence of dynamin-related protein 1 (Drp1)-regulated T cells on the antitumor effects of poly (ADP-ribose) polymerase inhibitors (PARPi) combined with programmed cell death protein 1 (PD-1) inhibitors to identify potential targets for enhancing immunotherapy efficacy. We found that T cells with high expression of Drp1 promoted the inhibitory and killing effects of the PARPi and PD-1 inhibitor combination on lung cancer cells in vivo and in vitro. This synergistic mechanism involves Drp1-regulated promotion of activation, migration, and intratumor infiltration of effector T cells; inhibition of negative immunomodulatory cells in the tumor microenvironment; and suppression of PARPi-induced upregulation of PD-L1 expression in tumor cells. These findings suggest that Drp1 could serve as a new target for comprehensively improving the tumor microenvironment, enhancing immunotherapy efficacy, and reversing immunotherapy resistance.
    Keywords:  Dynamin-related protein 1; Lung cancer; PARP inhibitor; PD-1 inhibitor; Tumor microenvironment
  38. J Immunother Cancer. 2024 Apr 12. pii: e008261. [Epub ahead of print]12(4):
      BACKGROUND: Chimeric antigen receptor (CAR) T-cell therapy target receptor tyrosine kinase-like orphan receptor 1 (ROR1) is broadly expressed in hematologic and solid tumors, however clinically-characterized ROR1-CAR T cells with single chain variable fragment (scFv)-R12 targeting domain failed to induce durable remissions, in part due to the immunosuppressive tumor microenvironment (TME). Herein, we describe the development of an improved ROR1-CAR with a novel, fully human scFv9 targeting domain, and augmented with TGFβRIIDN armor protective against a major TME factor, transforming growth factor beta (TGFβ).METHODS: CAR T cells were generated by lentiviral transduction of enriched CD4+ and CD8+ T cells, and the novel scFv9-based ROR1-CAR-1 was compared with the clinically-characterized ROR1-R12-scFv-based CAR-2 in vitro and in vivo.
    RESULTS: CAR-1 T cells exhibited greater CAR surface density than CAR-2 when normalized for %CAR+, and produced more interferon (IFN)-γ tumor necrosis factor (TNF)-α and interleukin (IL)-2 in response to hematologic (Jeko-1, RPMI-8226) and solid (OVCAR-3, Capan-2, NCI-H226) tumor cell lines in vitro. In vivo, CAR-1 and CAR-2 both cleared hematologic Jeko-1 lymphoma xenografts, however only CAR-1 fully rejected ovarian solid OVCAR-3 tumors, concordantly with greater expansion of CD8+ and CD4+CAR T cells, and enrichment for central and effector memory phenotype. When equipped with TGFβ-protective armor TGFβRIIDN, CAR-1 T cells resisted TGFβ-mediated pSmad2/3 phosphorylation, as compared with CAR-1 alone. When co-cultured with ROR-1+ AsPC-1 pancreatic cancer line in the presence of TGFβ1, armored CAR-1 demonstrated improved recovery of killing function, IFN-γ, TNF-α and IL-2 secretion. In mouse AsPC-1 pancreatic tumor xenografts overexpressing TGFβ1, armored CAR-1, in contrast to CAR-1 alone, achieved complete tumor remissions, and yielded accelerated expansion of CAR+ T cells, diminished circulating active TGFβ1, and no apparent toxicity or weight loss. Unexpectedly, in AsPC-1 xenografts without TGFβ overexpression, TGFβ1 production was specifically induced by ROR-1-CAR T cells interaction with ROR-1 positive tumor cells, and the TGFβRIIDN armor conferred accelerated tumor clearance.
    CONCLUSIONS: The novel fully human TGFßRIIDN-armored ROR1-CAR-1 T cells are highly potent against ROR1-positive tumors, and withstand the inhibitory effects of TGFß in solid TME. Moreover, TGFβ1 induction represents a novel, CAR-induced checkpoint in the solid TME, which can be circumvented by co-expressing the TGβRIIDN armor on T cells.
    Keywords:  Cell Engineering; Immunotherapy, Adoptive; Receptors, Chimeric Antigen; T-Lymphocytes; Tumor Microenvironment
  39. Cancer Manag Res. 2024 ;16 259-268
      Background: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer. Metformin has been shown to have the potential to inhibit the proliferation of malignant cells. This study aimed to investigate the regulatory effect of metformin on the expression of programmed death protein ligand 1(PD-L1) and mechanisms in TNBC.Methods: Mouse breast cancer cell line 4T1 was co-cultured with metformin, and the effect of metformin on cell proliferation was detected by MTT assay. The effect of metformin on the expression of JNK, RSK2 and CREB was detected by MAPK pathway protein chip. BALB/c mice were inoculated with 4T1 cells with knockdown/overexpression of C-Jun N-terminal kinase (JNK), and administered with metformin. The weight of tumor tissue was observed at the end of the experiment. The expression of PD-L1 in tumor cells was observed by immunofluorescence staining and the level of INF-γwas quantitatively determined by ELISA.
    Results: Metformin inhibited the viability of 4T1 cells and increased the phosphorylation of JNK to reduce the phosphorylation of RSK2 and CREB. Metformin and JNK knockdown reduced the expression of PD-L1 in tumor cells, but there was no significant difference in the weight of tumor tissue. Metformin can reduce the level of INF-γ in tumor tissues, but JNK has no effect.
    Conclusion: Metformin can inhibit the expression of PD-L1 in triple-negative breast cancer mice and improve the tumor microenvironment, but does not reduce the size of the tumor.
    Keywords:  C-Jun amino-terminal kinase; cell programmed death ligand 1; metformin; triple negative breast cancer
  40. Transplant Cell Ther. 2024 Apr 06. pii: S2666-6367(24)00343-9. [Epub ahead of print]
      Chimeric antigen receptor (CAR) T cell therapy has demonstrated remarkable efficacy in relapsed/refractory (r/r) B cell malignancies, including in pediatric patients with acute lymphoblastic leukemia (ALL). Expanding this success to other hematologic and solid malignancies is an area of active research and, although challenges remain, novel solutions have led to significant progress over the past decade. Ongoing clinical trials for CAR T cell therapy for T cell malignancies and acute myeloid leukemia (AML) have highlighted challenges, including antigen specificity with off-tumor toxicity and persistence concerns. In T cell malignancies, notable challenges include CAR T cell fratricide and prolonged T cell aplasia, which are being addressed with strategies such as gene editing and suicide switch technologies. In AML, antigen identification remains a significant barrier, due to shared antigens across healthy hematopoietic progenitor cells and myeloid blasts. Strategies to limit persistence and circumvent the immunosuppressive tumor microenvironment (TME) created by AML are also being explored. CAR T cell therapies for central nervous system and solid tumors have several challenges, including tumor antigen heterogeneity, immunosuppressive and hypoxic TME, and potential for off-target toxicity. Numerous CAR T cell products have been designed to overcome these challenges, including "armored" CARs and CAR/T cell receptor (TCR) hybrids. Strategies to enhance CAR T cell delivery, augment CAR T cell performance in the TME, and ensure the safety of these products have shown promising results. In this manuscript, we will review the available evidence for CAR T cell use in T cell malignancies, AML, central nervous system (CNS) and non-CNS solid tumor malignancies, and recommend areas for future research.
    Keywords:  CAR T cell therapy; CNS tumors; T cell malignancies; acute myeloid leukemia; solid tumors
  41. Asian J Pharm Sci. 2024 Apr;19(2): 100902
      With the rapid development of the fields of tumor biology and immunology, tumor immunotherapy has been used in clinical practice and has demonstrated significant therapeutic potential, particularly for treating tumors that do not respond to standard treatment options. Despite its advances, immunotherapy still has limitations, such as poor clinical response rates and differences in individual patient responses, largely because tumor tissues have strong immunosuppressive microenvironments. Many tumors have a tumor microenvironment (TME) that is characterized by hypoxia, low pH, and substantial numbers of immunosuppressive cells, and these are the main factors limiting the efficacy of antitumor immunotherapy. The TME is crucial to the occurrence, growth, and metastasis of tumors. Therefore, numerous studies have been devoted to improving the effects of immunotherapy by remodeling the TME. Effective regulation of the TME and reversal of immunosuppressive conditions are effective strategies for improving tumor immunotherapy. The use of multidrug combinations to improve the TME is an efficient way to enhance antitumor immune efficacy. However, the inability to effectively target drugs decreases therapeutic effects and causes toxic side effects. Nanodrug delivery carriers have the advantageous ability to enhance drug bioavailability and improve drug targeting. Importantly, they can also regulate the TME and deliver large or small therapeutic molecules to decrease the inhibitory effect of the TME on immune cells. Therefore, nanomedicine has great potential for reprogramming immunosuppressive microenvironments and represents a new immunotherapeutic strategy. Therefore, this article reviews strategies for improving the TME and summarizes research on synergistic nanomedicine approaches that enhance the efficacy of tumor immunotherapy.
    Keywords:  Nanomedicine; Tumor immunotherapy; Tumor microenvironment; Tumor reprogramming
  42. Cell Biochem Funct. 2024 Apr;42(3): e4010
      Mesenchymal stromal cells (MSCs) together with malignant cells present in the tumor microenvironment (TME), participate in the suppression of the antitumor immune response through the production of immunosuppressive factors, such as transforming growth factor beta 1 (TGF-β1). In previous studies, we reported that adenosine (Ado), generated by the adenosinergic activity of cervical cancer (CeCa) cells, induces the production of TGF-β1 by interacting with A2AR/A2BR. In the present study, we provide evidence that Ado induces the production of TGF-β1 in MSCs derived from CeCa tumors (CeCa-MSCs) by interacting with both receptors and that TGF-β1 acts in an autocrine manner to induce the expression of programmed death ligand 1 (PD-L1) in CeCa-MSCs, resulting in an increase in their immunosuppressive capacity on activated CD8+ T lymphocytes. The addition of the antagonists ZM241385 and MRS1754, specific for A2AR and A2BR, respectively, or SB-505124, a selective TGF-β1 receptor inhibitor, in CeCa-MSC cultures significantly inhibited the expression of PD-L1. Compared with CeCa-MSCs, MSCs derived from normal cervical tissue (NCx-MSCs), used as a control and induced with Ado to express PD-L1, showed a lower response to TGF-β1 to increase PD-L1 expression. Those results strongly suggest the presence of a feedback mechanism among the adenosinergic pathway, the production of TGF-β1, and the induction of PD-L1 in CeCa-MSCs to suppress the antitumor response of CD8+ T lymphocytes. The findings of this study suggest that this pathway may have clinical importance as a therapeutic target.
    Keywords:  CD8+ lymphocytes; PD‐L1; cervical cancer; immunosuppression; mesenchymal stromal cells
  43. Biochim Biophys Acta Mol Basis Dis. 2024 Apr 06. pii: S0925-4439(24)00148-0. [Epub ahead of print]1870(5): 167159
      Chimeric antigen receptor T (CAR-T) cell therapy is regarded as a potent immunotherapy and has made significant success in hematologic malignancies by eliciting antigen-specific immune responses. However, response rates of CAR-T cell therapy against solid tumors with immunosuppressive microenvironments remain limited. Co-engineering strategies are advancing methods to overcome immunosuppressive barriers and enhance antitumor responses. Here, we engineered an IL-2 mutein co-engineered CAR-T for the improvement of CAR-T cells against solid tumors and the efficient inhibition of solid tumors. We equipped the CAR-T cells with co-expressing both tumor antigen-targeted CAR and a mutated human interleukin-2 (IL-2m), conferring enhanced CAR-T cells fitness in vitro, reshaped immune-excluded TME, enhanced CAR-T infiltration in solid tumors, and improved tumor control without significant systemic toxicity. Overall, this subject demonstrates the universal CAR-T cells armed strategy for the development and optimization of CAR-T cells against solid tumors.
    Keywords:  Adoptive cellular immunotherapy; Cell engineering; Cytokine; T cell; Tumor microenvironment
  44. Cancers (Basel). 2024 Apr 04. pii: 1415. [Epub ahead of print]16(7):
      Hepatocellular carcinoma (HCC) is the most common primary liver cancer. It is a major public health problem worldwide, and it is often diagnosed at advanced stages, when no effective treatment options are available. Extracellular vesicles (EVs) are nanosized double-layer lipid vesicles containing various biomolecule cargoes, such as lipids, proteins, and nucleic acids. EVs are released from nearly all types of cells and have been shown to play an important role in cell-to-cell communication. In recent years, many studies have investigated the role of EVs in cancer, including HCC. Emerging studies have shown that EVs play primary roles in the development and progression of cancer, modulating tumor growth and metastasis formation. Moreover, it has been observed that non-coding RNAs (ncRNAs) carried by tumor cell-derived EVs promote tumorigenesis, regulating the tumor microenvironment (TME) and playing critical roles in the progression, angiogenesis, metastasis, immune escape, and drug resistance of HCC. EV-related ncRNAs can provide information regarding disease status, thus encompassing a role as biomarkers. In this review, we discuss the main roles of ncRNAs present in HCC-derived EVs, including micro(mi) RNAs, long non-coding (lnc) RNAs, and circular (circ) RNAs, and their potential clinical value as biomarkers and therapeutic targets.
    Keywords:  biomarkers; circular (circ) RNAs; drug resistance; extracellular vesicles (EV); hepatocellular carcinoma (HCC); immune escape; long non-coding (lnc) RNAs; micro(mi) RNAs; non-coding RNAs; tumor progression