bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2023–08–20
25 papers selected by
Peio Azcoaga, Biodonostia HRI
  1. Eosinophils in the tumor microenvironment: implications for cancer immunotherapy.
  2. Chemokines and receptors in the development and progression of malignant tumors.
  3. MicroRNAs mediated interaction of tumor microenvironment cells with breast cancer cells during bone metastasis.
  4. Tissue-resident macrophages - early passengers or drivers in the tumor niche?
  5. A CSF-1R-blocking antibody/IL-10 fusion protein increases anti-tumor immunity by effectuating tumor-resident CD8+ T cells.
  6. Targeting Macrophages for Tumor Therapy.
  7. The effect of resveratrol, curcumin and quercetin combination on immuno-suppression of tumor microenvironment for breast tumor-bearing mice.
  8. SOCS3 deletion in effector T cells confers an anti-tumorigenic role of IL-6 to the pro-tumorigenic cytokine.
  9. Editorial: Dual role of inflammatory mediators in cancer immunotherapy.
  10. Platinum(IV) Complexes as Inhibitors of STAT3 and Regulators of the Tumor Microenvironment To Control Breast Cancer.
  11. The extracellular vesicles targeting tumor microenvironment: a promising therapeutic strategy for melanoma.
  12. Glioma-neuronal circuit remodeling induces regional immunosuppression.
  13. Mini-Review: Enteric glia of the tumor microenvironment: An affair of corruption.
  14. Non-immune cell components in tumor microenvironment influencing lung cancer Immunotherapy.
  15. Extracellular vesicles targeting tumor microenvironment in ovarian cancer.
  16. Modulation of cancer-associated fibroblasts by nanodelivery system to enhance efficacy of tumor therapy.
  17. The current status of tumor microenvironment and cancer stem cells in sorafenib resistance of hepatocellular carcinoma.
  18. L-Kynurenine participates in cancer immune evasion by downregulating hypoxic signaling in T lymphocytes.
  19. m6A-regulated tumor glycolysis: new advances in epigenetics and metabolism.
  20. Targeting sphingosine 1-phosphate receptor 3 inhibits T-cell exhaustion and regulates recruitment of proinflammatory macrophages to improve antitumor efficacy of CAR-T cells against solid tumor.
  21. The link between intracellular calcium signaling and exosomal PD-L1 in cancer progression and immunotherapy.
  22. Bursting Tumor Bubbles to Improve CAR T-cell Therapy.
  23. Coagulation factor FVIIa enhances PD-L1 expression and its stability in breast cancer cells to promote breast cancer immune evasion.
  24. Mechanisms of Resistance to Chimeric Antigen Receptor T Cell Therapy.
  25. Single-cell analyses reveal cannabidiol rewires tumor microenvironment via inhibiting alternative activation of macrophage and synergizes with anti-PD-1 in colon cancer.
  1. J Transl Med. 2023 Aug 16. 21(1): 551
    Eosinophils in the tumor microenvironment: implications for cancer immunotherapy.
    Sasan Ghaffari, Nima Rezaei.
      Despite being an integral part of the immune response in the tumor microenvironment (TME), few studies have mechanistically elucidated eosinophil functions in cancer outcomes. Eosinophils are a minor population of granulocytes that are mostly explored in asthma and allergic disorders. Their influence on primary and metastatic tumors, however, has recently come to light. Eosinophils' diverse armamentarium of mediators and receptors allows them to participate in innate and adaptive immunity, such as type 1 and type 2 immunity, and shape TME and tumor outcomes. Based on TME cells and cytokines, activated eosinophils drive other immune cells to ultimately promote or suppress tumor growth. Discovering exactly what conditions determine the pro-tumorigenic or anti-tumorigenic role of eosinophils allows us to take advantage of these signals and devise novel strategies to target cancer cells. Here, we first revisit eosinophil biology and differentiation as recognizing eosinophil mediators is crucial to their function in homeostatic and pathological conditions as well as tumor outcome. The bulk of our paper discusses eosinophil interactions with tumor cells, immune cells-including T cells, plasma cells, natural killer (NK) cells-and gut microbiota. Eosinophil mediators, such as IL-5, IL-33, granulocyte-macrophage colony-stimulating factor (GM-CSF), thymic stromal lymphopoietin (TSLP), and CCL11 also determine eosinophil behavior toward tumor cells. We then examine the implications of these findings for cancer immunotherapy approaches, including immune checkpoint blockade (ICB) therapy using immune checkpoint inhibitors (ICIs) and chimeric antigen receptor (CAR) T cell therapy. Eosinophils synergize with CAR T cells and ICB therapy to augment immunotherapies.
    Keywords:  Adoptive cell therapy; Eosinophil; Immunotherapy; T cell; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s12967-023-04418-7
  2. Cytokine. 2023 Aug 15. pii: S1043-4666(23)00213-2. [Epub ahead of print]170 156335
    Chemokines and receptors in the development and progression of malignant tumors.
    Han-Qing Zhao, Jun Jiang.
      Cancer cells, endothelial cells, inflammatory cells and various cytokines form a part of the tumor microenvironment (TME). Chemokines constitute the largest family of cytokines, and are mainly secreted by tumor cells and inflammatory cells in the TME. They play an important role in tumor development and progression by promoting tumor growth and metastasis, angiogenesis, and targeting the chemoattraction of inflammatory cells. Currently, some chemokine receptor antagonists are being used in clinical trials as targeted anti-tumor drugs. In this article, we review the roles of chemokines in the development and progression of malignant tumors based on recently published papers, taking into consideration of the new anti-tumor therapeutic strategies targeting chemokines and receptors.
    Keywords:  Chemokines; Immunotherapy; Malignant Tumors; Tumor Microenvironment
    DOI:  https://doi.org/10.1016/j.cyto.2023.156335
  3. Breast Cancer. 2023 Aug 14.
    MicroRNAs mediated interaction of tumor microenvironment cells with breast cancer cells during bone metastasis.
    R L Akshaya, I Saranya, N Selvamurugan.
      Breast cancer (BC) bone metastasis is primarily osteolytic and has limited therapeutic options. Metastasized BC cells prime the secondary environment in bone by forming a tumor niche, which favors their homing and colonization. The tumor microenvironment (TME) is primarily generated by the cancer cells. Bone TME is an intricate network of multiple cells, including altered bone, tumor, stromal, and immune cells. Recent findings highlight the significance of small non-coding microRNAs (miRNAs) in influencing TME during tumor metastasis. MiRNAs from TME-resident cells facilitate the interaction between the tumor and its microenvironment, thereby regulating the biological processes of tumors. These miRNAs can serve as oncogenes or tumor suppressors. Hence, both miRNA inhibitors and mimics are extensively utilized in pre-clinical trials for modulating the phenotypes of tumor cells and associated stromal cells. This review briefly summarizes the recent developments on the functional role of miRNAs secreted directly or indirectly from the TME-resident cells in facilitating tumor growth, progression, and metastasis. This information would be beneficial in developing novel targeted therapies for BC.
    Keywords:  Bone metastasis; Breast cancer; Immune cells; Tumor microenvironment; miRNAs
    DOI:  https://doi.org/10.1007/s12282-023-01491-0
  4. Curr Opin Biotechnol. 2023 Aug 10. pii: S0958-1669(23)00094-0. [Epub ahead of print]83 102984
    Tissue-resident macrophages - early passengers or drivers in the tumor niche?
    Andrea Vogel, Thomas Weichhart.
      Macrophages within the tumor microenvironment of solid tumors and metastasis are heterogeneous populations, which contribute to diverse steps of tumorigenesis. Tumor-associated macrophages (TAMs) can either derive from circulation-derived monocytes or tissue-resident macrophages (TRMs). In health, TRMs populate the majority of tissues, orchestrating critical homeostatic and reparative functions. While TRM-specific functions in tumor initiation and progression remain unclear, recent studies have revealed that TRMs are a significant source of TAMs in both mouse and human cancers, where they closely resemble gene signatures of their normal, organ-specific TRM counterparts. In this review, we highlight recent advances toward systematically understanding the role of TRMs as an important TAM subset and opportunities how this macrophage population could be exploited for therapeutical targeting strategies.
    DOI:  https://doi.org/10.1016/j.copbio.2023.102984
  5. Cell Rep Med. 2023 Aug 15. pii: S2666-3791(23)00307-5. [Epub ahead of print]4(8): 101154
    A CSF-1R-blocking antibody/IL-10 fusion protein increases anti-tumor immunity by effectuating tumor-resident CD8+ T cells.
    Yao-Wen Chang, Huey-Wen Hsiao, Ju-Pei Chen, Sheue-Fen Tzeng, Chin-Hsien Tsai, Chun-Yi Wu, Hsin-Hua Hsieh, Santiago J Carmona, Massimo Andreatta, Giusy Di Conza, Mei-Tzu Su, Pandelakis A Koni, Ping-Chih Ho, Hung-Kai Chen, Muh-Hwa Yang.
      Strategies to increase intratumoral concentrations of an anticancer agent are desirable to optimize its therapeutic potential when said agent is efficacious primarily within a tumor but also have significant systemic side effects. Here, we generate a bifunctional protein by fusing interleukin-10 (IL-10) to a colony-stimulating factor-1 receptor (CSF-1R)-blocking antibody. The fusion protein demonstrates significant antitumor activity in multiple cancer models, especially head and neck cancer. Moreover, this bifunctional protein not only leads to the anticipated reduction in tumor-associated macrophages but also triggers proliferation, activation, and metabolic reprogramming of CD8+ T cells. Furthermore, it extends the clonotype diversity of tumor-infiltrated T cells and shifts the tumor microenvironment (TME) to an immune-active state. This study suggests an efficient strategy for designing immunotherapeutic agents by fusing a potent immunostimulatory molecule to an antibody targeting TME-enriched factors.
    Keywords:  CD8 T cell; TCR repertoire; colony-stimulating factor 1-receptor; head and neck cancer; immunotherapy; interleukin-10; macrophage; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.xcrm.2023.101154
  6. AAPS J. 2023 Aug 17. 25(5): 80
    Targeting Macrophages for Tumor Therapy.
    Yixin Wang, Allie Barrett, Quanyin Hu.
      Macrophages, as one of the most abundant tumor-infiltrating cells, play an important role in tumor development and metastasis. The frequency and polarization of tumor-associated macrophages (TAMs) correlate with disease progression, tumor metastasis, and resistance to various treatments. Pro-inflammatory M1 macrophages hold the potential to engulf tumor cells. In contrast, anti-inflammatory M2 macrophages, which are predominantly present in tumors, potentiate tumor progression and immune escape. Targeting macrophages to modulate the tumor immune microenvironment can ameliorate the tumor-associated immunosuppression and elicit an anti-tumor immune response. Strategies to repolarize TAMs, deplete TAMs, and block inhibitory signaling hold great potential in tumor therapy. Besides, biomimetic carriers based on macrophages have been extensively explored to prolong circulation, enhance tumor-targeted delivery, and reduce the immunogenicity of therapeutics to augment therapeutic efficacy. Moreover, the genetic engineering of macrophages with chimeric antigen receptor (CAR) allows them to recognize tumor antigens and perform tumor cell-specific phagocytosis. These strategies will expand the toolkit for treating tumors, especially for solid tumors, drug-resistant tumors, and metastatic tumors. Herein, we introduce the role of macrophages in tumor progression, summarize the recent advances in macrophage-centered anticancer therapy, and discuss their challenges as well as future applications. Graphical abstract.
    Keywords:  cell engineering; drug delivery; macrophages; tumor therapy
    DOI:  https://doi.org/10.1208/s12248-023-00845-y
  7. Sci Rep. 2023 08 16. 13(1): 13278
    The effect of resveratrol, curcumin and quercetin combination on immuno-suppression of tumor microenvironment for breast tumor-bearing mice.
    Chenchen Li, Yajun Xu, Junfeng Zhang, Yuxi Zhang, Wen He, Jiale Ju, Yinghua Wu, Yanli Wang.
      Resveratrol, curcumin, and quercetin are the secondary metabolites from medicinal food homology plants, that have been proven their potency in cancer treatment. However, the antitumor effect of a single component is weak. So, herein, we designed an antitumor compound named RCQ composed of resveratrol, curcumin, and quercetin. This study examined the effect on tumorigenesis and development of 4T1 breast cancer-bearing mice following administering RCQ by intragastric administration. RCQ increased the recruitment of T cells and reduced the accumulation of neutrophils and macrophages in the tumor microenvironment. Meanwhile, RCQ suppressed the development of tumor-infiltrating lymphocytes into immunosuppressive cell subpopulations, including CD4+ T cells to T helper Type 2 type (Th2), tumor-associated neutrophils (TANs) to the N2 TANs, and tumor-associated macrophages (TAMs) cells to M2 TAMs. RCQ reversed the predominance of immunosuppressive infiltrating cells in the tumor microenvironment and tipped the immune balance toward an immune activation state. In vitro the study showed that RCQ significantly increased reactive oxygen species (ROS), reduce mitochondrial membrane potentials in cancer cells, and modulate pro-apoptotic Bcl-2 family members. In conclusion, RCQ can promote the ROS apoptosis mechanism of tumor cells and alleviate immunosuppression of the tumor microenvironment to enhance the anti-tumor effect.
    DOI:  https://doi.org/10.1038/s41598-023-39279-z
  8. Cell Rep. 2023 Aug 08. pii: S2211-1247(23)00951-8. [Epub ahead of print] 112940
    SOCS3 deletion in effector T cells confers an anti-tumorigenic role of IL-6 to the pro-tumorigenic cytokine.
    Setsuko Mise-Omata, Makoto Ando, Tanakorn Srirat, Kensuke Nakagawara, Taeko Hayakawa, Mana Iizuka-Koga, Hiroshi Nishimasu, Osamu Nureki, Minako Ito, Akihiko Yoshimura.
      Interleukin (IL)-6 is abundantly expressed in the tumor microenvironment and is associated with poor patient outcomes. Here, we demonstrate that the deletion of the suppressor of cytokine signaling 3 (SOCS3) in T cells potentiates anti-tumor immune responses by conferring the anti-tumorigenic function of IL-6 in mouse and human models. In Socs3-deficient CD8+ T cells, IL-6 upregulates the expression of type I interferon (IFN)-regulated genes and enhances the anti-tumor effector function of T cells, while also modifying mitochondrial fitness to increase mitochondrial membrane potential and reactive oxygen species (ROS) levels and to promote metabolic glycolysis in the energy state. Furthermore, Socs3 deficiency reduces regulatory T cells and increases T helper 1 (Th1) cells. SOCS3 knockdown in human chimeric antigen receptor T (CAR-T) cells exhibits a strong anti-tumor response in humanized mice. Thus, genetic disruption of SOCS3 offers an avenue to improve the therapeutic efficacy of adoptive T cell therapy.
    Keywords:  CAR-T therapy; CP: Cancer; IL-6; anti-tumor immunity; cytotoxic T cell; effector T cells; mitochondrial fitness; regulatory T cells; suppressor of cytokine signaling 3
    DOI:  https://doi.org/10.1016/j.celrep.2023.112940
  9. Front Immunol. 2023 ;14 1229355
    Editorial: Dual role of inflammatory mediators in cancer immunotherapy.
    Xiaoli Wang, Jiashuai He, Jinghua Pan.
      
    Keywords:  cancer immunotherapy; dual role; inflammatory mediators; tumor microenvironment; tumor mutation burden
    DOI:  https://doi.org/10.3389/fimmu.2023.1229355
  10. J Med Chem. 2023 Aug 14.
    Platinum(IV) Complexes as Inhibitors of STAT3 and Regulators of the Tumor Microenvironment To Control Breast Cancer.
    Linxiang Cai, Ying Wang, Hanhua Chen, Yehong Tan, Tao Yang, Shuren Zhang, Zijian Guo, Xiaoyong Wang.
      Interplay between breast cancer (BC) cells and the tumor microenvironment (TME) influences the outcome of cancer treatment. Aberrant activation of signal transducer and activator of transcription 3 (STAT3) promotes the interaction and causes immunosuppression and drug resistance. Platinum(IV) complexes SPP and DPP bearing pterostilbene-derived axial ligand(s) were synthesized to inhibit the JAK2-STAT3 pathway in BC cells and regulate the TME. These complexes exerted remarkable antiproliferative activity against the triple-negative BC cells, suppressed the expression of phosphorylated STAT3 and STAT3-related cyclooxygenase-2 and IL-6, and activated caspase-3 and cleaved poly ADP-ribose polymerase, preventing the repair of DNA lesions and inducing apoptosis. Furthermore, DPP promoted the maturation and antigen presentation of dendritic cells, repressed the proliferation and differentiation of myeloid-derived suppressor cells and regulatory T cells, and facilitated the expansion of T cells. As a consequence, DPP showed excellent anticancer activity against BC with almost no general toxicity in vivo as a potential chemoimmunotherapeutic agent.
    DOI:  https://doi.org/10.1021/acs.jmedchem.3c00836
  11. Front Immunol. 2023 ;14 1200249
    The extracellular vesicles targeting tumor microenvironment: a promising therapeutic strategy for melanoma.
    Yongmin Li, Fei Liu.
      Extracellular vesicles (EVs) are small particles secreted by numerous cell types and circulate in almost all body fluids, acting as crucial messengers for cell-to-cell communication. EVs involves multiple physiological and pathological processes, including tumor progression, via their multiple cargoes. Therefore, EVs have become attractive candidates for the treatment of tumor, including melanoma. Notably, due to the crucial role of the tumor microenvironment (TME) in promoting tumor malignant phenotype, and the close intercellular communication in TME, EVs-based therapy by targeting TME has become a cutting-edge and prospective strategy for inhibiting melanoma progression and strengthening the anti-tumor immunity. In this review, we aimed to summarize and discuss the role of therapeutic EVs, which target the components of TME in melanoma, thereby providing insights into these promising clinical strategies for the treatment of melanoma patients.
    Keywords:  cancer; extracellular vesicles; immunotherapy; melanoma; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2023.1200249
  12. bioRxiv. 2023 Aug 06. pii: 2023.08.04.548295. [Epub ahead of print]
    Glioma-neuronal circuit remodeling induces regional immunosuppression.
    Takahide Nejo, Saritha Krishna, Christian Jimenez, Akane Yamamichi, Jacob S Young, Senthilnath Lakshmanachetty, Tiffany Chen, Su Su Sabai Phyu, Hirokazu Ogino, Payal Watchmaker, David Diebold, Abrar Choudhury, Andy G S Daniel, David R Raleigh, Shawn L Hervey-Jumper, Hideho Okada.
      Neuronal activity-driven mechanisms impact glioblastoma cell proliferation and invasion 1-7 , and glioblastoma remodels neuronal circuits 8,9 . Distinct intratumoral regions maintain functional connectivity via a subpopulation of malignant cells that mediate tumor-intrinsic neuronal connectivity and synaptogenesis through their transcriptional programs 8 . However, the effects of tumor-intrinsic neuronal activity on other cells, such as immune cells, remain unknown. Here we show that regions within glioblastomas with elevated connectivity are characterized by regional immunosuppression. This was accompanied by different cell compositions and inflammatory status of tumor-associated macrophages (TAMs) in the tumor microenvironment. In preclinical intracerebral syngeneic glioblastoma models, CRISPR/Cas9 gene knockout of Thrombospondin-1 (TSP-1/ Thbs1 ), a synaptogenic factor critical for glioma-induced neuronal circuit remodeling, in glioblastoma cells suppressed synaptogenesis and glutamatergic neuronal hyperexcitability, while simultaneously restoring antigen-presentation and pro-inflammatory responses. Moreover, TSP-1 knockout prolonged survival of immunocompetent mice harboring intracerebral syngeneic glioblastoma, but not of immunocompromised mice, and promoted infiltrations of pro-inflammatory TAMs and CD8+ T-cells in the tumor microenvironment. Notably, pharmacological inhibition of glutamatergic excitatory signals redirected tumor-associated macrophages toward a less immunosuppressive phenotype, resulting in prolonged survival. Altogether, our results demonstrate previously unrecognized immunosuppression mechanisms resulting from glioma-neuronal circuit remodeling and suggest future strategies targeting glioma-neuron-immune crosstalk may open up new avenues for immunotherapy.
    DOI:  https://doi.org/10.1101/2023.08.04.548295
  13. Neurosci Lett. 2023 Aug 10. pii: S0304-3940(23)00375-0. [Epub ahead of print] 137416
    Mini-Review: Enteric glia of the tumor microenvironment: An affair of corruption.
    Chloe L Mariant, Gregory Bacola, Laurianne Van Landeghem.
      The tumor microenvironment corresponds to a complex mixture of bioactive products released by local and recruited cells whose normal functions have been "corrupted" by cues originating from the tumor, mostly to favor cancer growth, dissemination and resistance to therapies. While the immune and the mesenchymal cellular components of the tumor microenvironment in colon cancers have been under intense scrutiny over the last two decades, the influence of the resident neural cells of the gut on colon carcinogenesis has only very recently begun to draw attention. The vast majority of the resident neural cells of the gastrointestinal tract belong to the enteric nervous system and correspond to enteric neurons and enteric glial cells, both of which have been understudied in the context of colon cancer development and progression. In this review, we especially discuss available evidence on enteric glia impact on colon carcinogenesis. To highlight "corrupted" functioning in enteric glial cells of the tumor microenvironment and its repercussion on tumorigenesis, we first review the main regulatory effects of enteric glial cells on the intestinal epithelium in homeostatic conditions and we next present current knowledge on enteric glia influence on colon tumorigenesis. We particularly examine how enteric glial cell heterogeneity and plasticity require further appreciation to better understand the distinct regulatory interactions enteric glial cell subtypes engage with the various cell types of the tumor, and to identify novel biological targets to block enteric glia pro-carcinogenic signaling.
    Keywords:  Cancer stem cell; Colon cancer; Enteric glial cell; Intestinal stem cell; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.neulet.2023.137416
  14. Biomed Pharmacother. 2023 Aug 15. pii: S0753-3322(23)01127-7. [Epub ahead of print]166 115336
    Non-immune cell components in tumor microenvironment influencing lung cancer Immunotherapy.
    Jingtao Zhang, Shuai Liu, Xiubao Chen, Xiangdong Xu, Fei Xu.
      Lung cancer (LC) is one of the leading causes of cancer-related deaths worldwide, with a significant morbidity and mortality rate, endangering human life and health. The introduction of immunotherapies has significantly altered existing cancer treatment strategies and is expected to improve immune responses, objective response rates, and survival rates. However, a better understanding of the complex immunological networks of LC is required to improve immunotherapy efficacy further. Tumor-associated antigens (TAAs) and tumor-specific antigens (TSAs) are significantly expressed by LC cells, which activate dendritic cells, initiate antigen presentation, and activate lymphocytes to exert antitumor activity. However, as tumor cells combat the immune system, an immunosuppressive microenvironment forms, enabling the enactment of a series of immunological escape mechanisms, including the recruitment of immunosuppressive cells and induction of T cell exhaustion to decrease the antitumor immune response. In addition to the direct effect of LC cells on immune cell function, the secreting various cytokines, chemokines, and exosomes, changes in the intratumoral microbiome and the function of cancer-associated fibroblasts and endothelial cells contribute to LC cell immune escape. Accordingly, combining various immunotherapies with other therapies can elicit synergistic effects based on the complex immune network, improving immunotherapy efficacy through multi-target action on the tumor microenvironment (TME). Hence, this review provides guidance for understanding the complex immune network in the TME and designing novel and effective immunotherapy strategies for LC.
    Keywords:  Adoptive T cell therapy; ICIs; Immunotherapy; LC; TME; Tumor vaccine
    DOI:  https://doi.org/10.1016/j.biopha.2023.115336
  15. Int J Biol Macromol. 2023 Aug 11. pii: S0141-8130(23)03196-3. [Epub ahead of print] 126300
    Extracellular vesicles targeting tumor microenvironment in ovarian cancer.
    Chunmei Zhang, Meiying Qin.
      Ovarian cancer (OC) is a prevalent neoplastic condition affecting women. Extracellular vesicles (EVs), nano-sized membrane vesicles, are secreted by various cells in both physiological and pathological states. The profound interplay between EVs and the tumor microenvironment (TME) in ovarian cancer is crucial. In this review, we explores the pivotal role of EVs in facilitating intercellular communication between cancer cells and the TME, emphasizing the potential of EVs as promising diagnostic markers and innovative therapeutic targets for ovarian cancer. The comprehensive analysis outlines the specific mechanisms by which EVs engage in communication with the constituents of the TME, including the modulation of tumor growth through EVs carrying matrix metalloproteinases (MMPs) and EV-mediated inhibition of angiogenesis, among other factors. Additionally, the we discuss the potential clinical applications of EVs that target the TME in ovarian cancer, encompassing the establishment of novel treatment strategies and the identification of novel biomarkers for early detection and prognosis. Finally, this review identifies novel strategies for therapeutic interventions, such as utilizing EVs as carriers for drug delivery and targeting specific EV-mediated signaling pathways. In summary, this manuscript offers valuable insights into the role of EVs in ovarian cancer and highlights the significance of comprehending intercellular communication in the realm of cancer biology.
    Keywords:  Extracellular vesicles; Intercommunication; Ovarian cancer; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.ijbiomac.2023.126300
  16. Nanomedicine (Lond). 2023 Jun;18(15): 1025-1039
    Modulation of cancer-associated fibroblasts by nanodelivery system to enhance efficacy of tumor therapy.
    Wei Ai, Tianhui Liu, Changshun Lv, Xiangru Feng, Qingshuang Wang.
      Cancer-associated fibroblasts (CAFs) are the most common cells in the tumor stroma and are essential for tumor development and metastasis. While decreasing the release and infiltration of nanomedicine through nonspecific internalization, CAFs specifically increase solid tumor pressure and interstitial fluid pressure by secreting tumor growth- and migration-promoting cytokines, which increases vascular and organ pressure caused by solid tumor pressure. Nanoparticles have good permeability and can penetrate tumor tissue to reach the lesion area, inhibiting tumor growth. Thus, CAFs are used as modifiable targets. Here, the authors review the biological functions, origins and biomarkers of CAFs and summarize strategies for modulating CAFs in nanodelivery systems. This study provides a prospective guide to modulating CAFs to enhance oncology treatment.
    Keywords:  ECM modulation; anticancer strategies; biological function; biomarkers; cancer-associated fibroblasts; extracellular matrix stress; immunosuppression; nano-delivery system; tumor microenvironment; tumor therapy
    DOI:  https://doi.org/10.2217/nnm-2023-0088
  17. Front Oncol. 2023 ;13 1204513
    The current status of tumor microenvironment and cancer stem cells in sorafenib resistance of hepatocellular carcinoma.
    Siqi Chen, Yaqing Du, Xin-Yuan Guan, Qian Yan.
      Hepatocellular carcinoma (HCC) is a heterogeneous and aggressive liver cancer that presents limited treatment options. Despite being the standard therapy for advanced HCC, sorafenib frequently encounters resistance, emphasizing the need to uncover the underlying mechanisms and develop effective treatments. This comprehensive review highlights the crucial interplay between the tumor microenvironment, cancer stem cells (CSCs), and epithelial-mesenchymal transition (EMT) in the context of sorafenib resistance. The tumor microenvironment, encompassing hypoxia, immune cells, stromal cells, and exosomes, exerts a significant impact on HCC progression and therapy response. Hypoxic conditions and immune cell infiltration create an immunosuppressive milieu, shielding tumor cells from immune surveillance and hindering therapeutic efficacy. Additionally, the presence of CSCs emerges as a prominent contributor to sorafenib resistance, with CD133+ CSCs implicated in drug resistance and tumor initiation. Moreover, CSCs undergo EMT, a process intimately linked to tumor progression, CSC activation, and further promotion of sorafenib resistance, metastasis, and tumor-initiating capacity. Elucidating the correlation between the tumor microenvironment, CSCs, and sorafenib resistance holds paramount importance in the quest to develop reliable biomarkers capable of predicting therapeutic response. Novel therapeutic strategies must consider the influence of the tumor microenvironment and CSC activation to effectively overcome sorafenib resistance in HCC.
    Keywords:  EMT; cancer stem cells; exosomes; hepatocellular carcinoma; hypoxia; immune microenvironment; sorafenib resistance; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2023.1204513
  18. Oncoimmunology. 2023 ;12(1): 2244330
    L-Kynurenine participates in cancer immune evasion by downregulating hypoxic signaling in T lymphocytes.
    Stephanie Schlichtner, Inna M Yasinska, Elena Klenova, Maryam Abooali, Gurprit S Lall, Steffen M Berger, Sabrina Ruggiero, Dietmar Cholewa, Milan Milošević, Bernhard F Gibbs, Elizaveta Fasler-Kan, Vadim V Sumbayev.
      Malignant tumors often escape anticancer immune surveillance by suppressing the cytotoxic functions of T lymphocytes. While many of these immune evasion networks include checkpoint proteins, small molecular weight compounds, such as the amino acid L-kynurenine (LKU), could also substantially contribute to the suppression of anti-cancer immunity. However, the biochemical mechanisms underlying the suppressive effects of LKU on T-cells remain unclear. Here, we report for the first time that LKU suppresses T cell function as an aryl hydrocarbon receptor (AhR) ligand. The presence of LKU in T cells is associated with AhR activation, which results in competition between AhR and hypoxia-inducible factor 1 alpha (HIF-1α) for the AhR nuclear translocator, ARNT, leading to T cell exhaustion. The expression of indoleamine 2,3-dioxygenase 1 (IDO1, the enzyme that leads to LKU generation) is induced by the TGF-β-Smad-3 pathway. We also show that IDO-negative cancers utilize an alternative route for LKU production via the endogenous inflammatory mediator, the high mobility group box 1 (HMGB-1)-interferon-gamma (IFN-γ) axis. In addition, other IDO-negative tumors (like T-cell lymphomas) trigger IDO1 activation in eosinophils present in the tumor microenvironment (TME). These mechanisms suppress cytotoxic T cell function, and thus support the tumor immune evasion machinery.
    Keywords:  T cells; cancer; immune checkpoints; immune escape; kynurenine
    DOI:  https://doi.org/10.1080/2162402X.2023.2244330
  19. Mol Cancer. 2023 08 15. 22(1): 137
    m6A-regulated tumor glycolysis: new advances in epigenetics and metabolism.
    Shi-Wei Yue, Hai-Ling Liu, Hong-Fei Su, Chu Luo, Hui-Fang Liang, Bi-Xiang Zhang, Wei Zhang.
      Glycolytic reprogramming is one of the most important features of cancer and plays an integral role in the progression of cancer. In cancer cells, changes in glucose metabolism meet the needs of self-proliferation, angiogenesis and lymphangiogenesis, metastasis, and also affect the immune escape, prognosis evaluation and therapeutic effect of cancer. The n6-methyladenosine (m6A) modification of RNA is widespread in eukaryotic cells. Dynamic and reversible m6A modifications are widely involved in the regulation of cancer stem cell renewal and differentiation, tumor therapy resistance, tumor microenvironment, tumor immune escape, and tumor metabolism. Lately, more and more evidences show that m6A modification can affect the glycolysis process of tumors in a variety of ways to regulate the biological behavior of tumors. In this review, we discussed the role of glycolysis in tumor genesis and development, and elaborated in detail the profound impact of m6A modification on different tumor by regulating glycolysis. We believe that m6A modified glycolysis has great significance and potential for tumor treatment.
    Keywords:  Glycolysis; Tumor; Tumor therapy; m6A
    DOI:  https://doi.org/10.1186/s12943-023-01841-8
  20. J Immunother Cancer. 2023 Aug;pii: e006343. [Epub ahead of print]11(8):
    Targeting sphingosine 1-phosphate receptor 3 inhibits T-cell exhaustion and regulates recruitment of proinflammatory macrophages to improve antitumor efficacy of CAR-T cells against solid tumor.
    Ge Gao, Weiting Liao, Pei Shu, Qizhi Ma, Xia He, Benxia Zhang, Diyuan Qin, Yongsheng Wang.
       BACKGROUNDS: Chimeric antigen receptor (CAR)-modified T cells (CAR-T) are limited in solid tumors due to the hostile tumor microenvironment (TME). Combination therapy could be a promising approach to overcome this obstacle. Recent studies have shown that sphingosine 1-phosphate receptor (S1PR)3 has tremendous potential in regulating the immune environment. However, the functional significance of S1PR3 in T-cell-based immunotherapies and the molecular mechanisms have not been fully understood.
    METHODS: Here, we studied the combination of EpCAM-specific CAR T-cell therapy with pharmacological blockade of S1PR3 against solid tumor. We have applied RNA sequencing, flow cytometry, ELISA, cellular/molecular immunological technology, and mouse models of solid cancers.
    RESULTS: Our study provided evidence that S1PR3 high expression is positively associated with resistance to programmed cell death protein-1 (PD-1)-based immunotherapy and increased T-cell exhaustion. In addition, pharmacological inhibition of S1PR3 improves the efficacy of anti-PD-1 therapy. Next, we explored the possible combination of S1PR3 antagonist with murine EpCAM-targeted CAR-T cells in immunocompetent mouse models of breast cancer and colon cancer. The results indicated that the S1PR3 antagonist could significantly enhance the efficacy of murine EpCAM CAR-T cells in vitro and in vivo. Mechanistically, the S1PR3 antagonist improved CAR-T cell activation, regulated the central memory phenotype, and reduced CAR-T cell exhaustion in vitro. Targeting S1PR3 was shown to remodel the TME through the recruitment of proinflammatory macrophages by promoting macrophage activation and proinflammatory phenotype polarization, resulting in improved CAR-T cell infiltration and amplified recruitment of CD8+T cells.
    CONCLUSIONS: This work demonstrated targeting S1PR3 could increase the antitumor activities of CAR-T cell therapy at least partially by inhibiting T-cell exhaustion and remodeling the TME through the recruitment of proinflammatory macrophages. These findings provided additional rationale for combining S1PR3 inhibitor with CAR-T cells for the treatment of solid tumor.
    Keywords:  immunotherapy; lymphocytes, tumor-infiltrating; macrophages; receptors, chimeric antigen; tumor microenvironment
    DOI:  https://doi.org/10.1136/jitc-2022-006343
  21. Genes Dis. 2024 Jan;11(1): 321-334
    The link between intracellular calcium signaling and exosomal PD-L1 in cancer progression and immunotherapy.
    Md Rakibul Alam, Md Mizanur Rahman, Zhiguo Li.
      Exosomes are small membrane vesicles containing microRNA, RNA, DNA fragments, and proteins that are transferred from donor cells to recipient cells. Tumor cells release exosomes to reprogram the factors associated with the tumor microenvironment (TME) causing tumor metastasis and immune escape. Emerging evidence revealed that cancer cell-derived exosomes carry immune inhibitory molecule program death ligand 1 (PD-L1) that binds with receptor program death protein 1 (PD-1) and promote tumor progression by escaping immune response. Currently, some FDA-approved monoclonal antibodies are clinically used for cancer treatment by blocking PD-1/PD-L1 interaction. Despite notable treatment outcomes, some patients show poor drug response. Exosomal PD-L1 plays a vital role in lowering the treatment response, showing resistance to PD-1/PD-L1 blockage therapy through recapitulating the effect of cell surface PD-L1. To enhance therapeutic response, inhibition of exosomal PD-L1 is required. Calcium signaling is the central regulator of tumorigenesis and can regulate exosome biogenesis and secretion by modulating Rab GTPase family and membrane fusion factors. Immune checkpoints are also connected with calcium signaling and calcium channel blockers like amlodipine, nifedipine, lercanidipine, diltiazem, and verapamil were also reported to suppress cellular PD-L1 expression. Therefore, to enhance the PD-1/PD-L1 blockage therapy response, the reduction of exosomal PD-L1 secretion from cancer cells is in our therapeutic consideration. In this review, we proposed a therapeutic strategy by targeting calcium signaling to inhibit the expression of PD-L1-containing exosome levels that could reduce the anti-PD-1/PD-L1 therapy resistance and increase the patient's drug response rate.
    Keywords:  CD8+T cells; Calcium signaling; Exosomal PD-L1; Exosomes biogenesis; Immunosuppression; Immunotherapy
    DOI:  https://doi.org/10.1016/j.gendis.2023.01.026
  22. Cancer Res. 2023 Aug 15. 83(16): 2637-2639
    Bursting Tumor Bubbles to Improve CAR T-cell Therapy.
    Sergio Ortiz-Espinosa, Shivani Srivastava.
      Chimeric antigen receptor (CAR) T cells have had dramatic success in B-cell malignancies, but this efficacy has not yet translated to more common solid tumors. In this issue of Cancer Research, Zhong and colleagues demonstrated that tumor-derived small extracellular vesicles (sEV) contain CAR target antigens like mesothelin, enabling them to preferentially interact with and suppress the activity of CAR T cells in vivo. PD-L1 in tumor-derived sEVs increased upon CAR T-cell infusion and induced PD-L1-dependent suppression of CAR T cells that could be completely reversed by PD-L1 blockade. Strategies to inhibit sEV secretion, via genetic manipulation of tumor cells or pharmacologic inhibition, significantly improved CAR T-cell accumulation, function, and antitumor activity in vivo, suggesting that therapeutic targeting of sEV secretion could be a promising new approach to improving the efficacy of CAR T-cell therapy. See related article by Zhong et al., p. 2790.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-1484
  23. J Thromb Haemost. 2023 Aug 12. pii: S1538-7836(23)00632-3. [Epub ahead of print]
    Coagulation factor FVIIa enhances PD-L1 expression and its stability in breast cancer cells to promote breast cancer immune evasion.
    Subhojit Paul, Kaushik Das, Arnab Ghosh, Akash Chatterjee, Avinandan Bhoumick, Abhimanyu Basu, Prosenjit Sen.
       BACKGROUND: Immunotherapy for breast cancer has not gained significant success. Coagulation factor FVIIa (FVIIa)-tissue factor (TF) mediated activation of protease-activated receptor 2 (PAR2) is shown to promote metastasis and secretion of the immune-modulatory cytokines but the role of FVIIa in cancer immunology is still not well understood.
    OBJECTIVES: Here, we aim to investigate whether FVIIa protects breast cancer cells from CD8 T cell-mediated killing.
    METHODS: Peripheral blood mononuclear cell (PBMC)-derived CD8 T cells were co-cultured with vehicle or FVIIa pre-treated MDAMB468 cells. The proliferation and activity of CD8 T cells were measured by flow cytometry and ELISA. An allograft model, using wild-type or TF/PAR2-deleted 4T1 cells, was employed to determine the effect of FVIIa on breast cancer immune evasion in vivo.
    RESULTS AND CONCLUSION: Here, we demonstrate that TF-FVIIa induces programmed death-ligand 1 (PD-L1) in breast cancer cells by activating PAR2. PAR2 activation triggers large tumor suppressor kinase 1 (LATS1) inactivation leading to loss of yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) phosphorylation and subsequent nuclear localization of YAP/TAZ. YAP/TAZ inhibition reduces PD-L1 expression and increases CD8 T cell activity. We further demonstrate that, apart from transcriptional induction of PD-L1, PAR2 activation also increases PD-L1 stability by enhancing its glycosylation through N-glycosyltransferases STT3A and STT3B. In a mouse model of breast cancer, tumor cell-specific PAR2 depletion leads to PD-L1 downregulation and increases anti-PD-1 immunotherapy efficacy. In conclusion, we show that FVIIa-mediated signaling cascade in cancer cells serves as a tumor intrinsic mechanism of immunosuppression to promote cancer immune evasion.
    Keywords:  CD8 T cells; breast cancer; coagulation factor FVIIa; immune evasion; protease-activated receptor 2; tissue factor
    DOI:  https://doi.org/10.1016/j.jtha.2023.08.008
  24. Hematol Oncol Clin North Am. 2023 Aug 12. pii: S0889-8588(23)00105-3. [Epub ahead of print]
    Mechanisms of Resistance to Chimeric Antigen Receptor T Cell Therapy.
    Grace A Johnson, Frederick L Locke.
      CAR T cell therapy has significantly shaped the treatment landscape for refractory hematologic malignancies including large B-cell lymphomas, multiple myeloma, and leukemias. While response rates for a previously dismal prognosis have improved, certain obstacles still remain to achieving CAR T infallibility. In this article, we review the data surrounding proposed resistance mechanisms of tumors to CAR T, including the implications of target loss, exhausted T cells as effete effectors, the necessity of maximal CAR T expansion to durable response, the negative impact of an inflammatory milieu and a suppressive tumor microenvironment, and the optimal tumor-to-effector ratio that associates with best outcomes. The future of CAR T should aim to mitigate these weaknesses in order to bolster the efficacy of this revolutionary therapy.
    Keywords:  Acute lymphocytic leukemia; CAR T-cell therapy; Cellular immunotherapy; Chronic lymphocytic leukemia; Large B-cell lymphoma; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.hoc.2023.07.003
  25. J Pharm Anal. 2023 Jul;13(7): 726-744
    Single-cell analyses reveal cannabidiol rewires tumor microenvironment via inhibiting alternative activation of macrophage and synergizes with anti-PD-1 in colon cancer.
    Xiaofan Sun, Lisha Zhou, Yi Wang, Guoliang Deng, Xinran Cao, Bowen Ke, Xiaoqi Wu, Yanhong Gu, Haibo Cheng, Qiang Xu, Qianming Du, Hongqi Chen, Yang Sun.
      Colorectal tumors often create an immunosuppressive microenvironment that prevents them from responding to immunotherapy. Cannabidiol (CBD) is a non-psychoactive natural active ingredient from the cannabis plant that has various pharmacological effects, including neuroprotective, antiemetic, anti-inflammatory, and antineoplastic activities. This study aimed to elucidate the specific anticancer mechanism of CBD by single-cell RNA sequencing (scRNA-seq) and single-cell ATAC sequencing (scATAC-seq) technologies. Here, we report that CBD inhibits colorectal cancer progression by modulating the suppressive tumor microenvironment (TME). Our single-cell transcriptome and ATAC sequencing results showed that CBD suppressed M2-like macrophages and promoted M1-like macrophages in tumors both in strength and quantity. Furthermore, CBD significantly enhanced the interaction between M1-like macrophages and tumor cells and restored the intrinsic anti-tumor properties of macrophages, thereby preventing tumor progression. Mechanistically, CBD altered the metabolic pattern of macrophages and related anti-tumor signaling pathways. We found that CBD inhibited the alternative activation of macrophages and shifted the metabolic process from oxidative phosphorylation and fatty acid oxidation to glycolysis by inhibiting the phosphatidylinositol 3-kinase-protein kinase B signaling pathway and related downstream target genes. Furthermore, CBD-mediated macrophage plasticity enhanced the response to anti-programmed cell death protein-1 (PD-1) immunotherapy in xenografted mice. Taken together, we provide new insights into the anti-tumor effects of CBD.
    Keywords:  Cannabidiol; Colorectal cancer; Macrophage; Tumor microenvironment; scATAC-seq; scRNA-seq
    DOI:  https://doi.org/10.1016/j.jpha.2023.04.013
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