bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2023–09–24
27 papers selected by
Peio Azcoaga, Biodonostia HRI
  1. Functional polarization of tumor-associated macrophages dictated by metabolic reprogramming.
  2. Extracellular matrix in cancer progression and therapy.
  3. Glutamine availability unleashes dendritic cells' anti-tumor power.
  4. Tumor-associated macrophages, dendritic cells, and neutrophils: biological roles, crosstalk, and therapeutic relevance.
  5. Escherichia coli adhesion portion FimH polarizes M2 macrophages to M1 macrophages in tumor microenvironment via toll-like receptor 4.
  6. Dietary fat and lipid metabolism in the tumor microenvironment.
  7. Immune evasion of G-CSF and GM-CSF in lung cancer.
  8. The diversity and dynamics of tumor-associated macrophages in recurrent glioblastoma.
  9. Understanding metabolic reprogramming in tumor microenvironment.
  10. Formate supplementation enhances anti-tumor CD8+ T cell fitness and efficacy of PD-1 blockade.
  11. Efficient TNBC immunotherapy by dual reprogramming tumor-infiltrating dendritic cells and tumor-associated macrophages with stimulus-responsive miR155 nanocomplexes.
  12. CD300ld on Neutrophils Drives Immune Suppression and Tumor Growth.
  13. JunB: a paradigm for Jun family in immune response and cancer.
  14. Interaction between N6-methyladenosine modification and the tumor microenvironment in colorectal cancer.
  15. Expressing CXCR4 in CAR-T cells Suppresses MDSCs Recruitment via STAT3/NF-κB/SDF-1α axis to enhance Anti-tumor Efficacy against Pancreatic Cancer.
  16. The tumor microenvironment shows a hierarchy of cell-cell interactions dominated by fibroblasts.
  17. Tumor lipid metabolism: a mechanistic link between diet and cancer progression.
  18. Extracellular vesicles in cancer: Shaping the intricate network of metabolic reprogramming and immune interactions in the tumor microenvironment.
  19. Extracellular pyruvate kinase M2 induces cell migration through p-Tyr42 RhoA-mediated superoxide generation and epithelial-mesenchymal transition.
  20. Role of tissue markers associated with tumor microenvironment in the progression and immune suppression of oral squamous cell carcinoma.
  21. Circulating tumor cells and host immunity: A tricky liaison.
  22. Insight into the Progress in CAR-T Cell Therapy and Combination with Other Therapies for Glioblastoma.
  23. The role of bone marrow microenvironment (BMM) cells in acute myeloid leukemia (AML) progression: immune checkpoints, metabolic checkpoints, and signaling pathways.
  24. Targeting intratumoral hypoxia to enhance anti-tumor immunity.
  25. Metabolic diversity of tumor-infiltrating T cells as target for anti-immune therapeutics.
  26. Cancer cell-intrinsic PD-1: Its role in malignant progression and immunotherapy.
  27. The role of platelets in the regulation of tumor growth and metastasis: the mechanisms and targeted therapy.
  1. J Exp Clin Cancer Res. 2023 Sep 23. 42(1): 245
    Functional polarization of tumor-associated macrophages dictated by metabolic reprogramming.
    Wentao Zeng, Fei Li, Shikai Jin, Ping-Chih Ho, Pu-Ste Liu, Xin Xie.
      Macrophages are highly plastic in different tissues and can differentiate into functional subpopulations under different stimuli. Tumor-associated macrophages (TAMs) are one of the most important innate immune cells implicated in the establishment of an immunosuppressive tumor microenvironment (TME). Recent evidence pinpoints the critical role of metabolic reprogramming in dictating pro-tumorigenic functions of TAMs. Both tumor cells and macrophages undergo metabolic reprogramming to meet energy demands in the TME. Understanding the metabolic rewiring in TAMs can shed light on immune escape mechanisms and provide insights into repolarizing TAMs towards anti-tumorigenic function. Here, we discuss how metabolism impinges on the functional divergence of macrophages and its relevance to macrophage polarization in the TME.
    Keywords:  Metabolic reprogramming; Polarization; Signaling pathways; TAMs; TME
    DOI:  https://doi.org/10.1186/s13046-023-02832-9
  2. Med Rev (Berl). 2022 Apr;2(2): 125-139
    Extracellular matrix in cancer progression and therapy.
    Xiuxiu He, Byoungkoo Lee, Yi Jiang.
      The tumor ecosystem with heterogeneous cellular compositions and the tumor microenvironment has increasingly become the focus of cancer research in recent years. The extracellular matrix (ECM), the major component of the tumor microenvironment, and its interactions with the tumor cells and stromal cells have also enjoyed tremendously increased attention. Like the other components of the tumor microenvironment, the ECM in solid tumors differs significantly from that in normal organs and tissues. We review recent studies of the complex roles the tumor ECM plays in cancer progression, from tumor initiation, growth to angiogenesis and invasion. We highlight that the biomolecular, biophysical, and mechanochemical interactions between the ECM and cells not only regulate the steps of cancer progression, but also affect the efficacy of systemic cancer treatment. We further discuss the strategies to target and modify the tumor ECM to improve cancer therapy.
    Keywords:  cancer invasion; cancer metabolism; cancer progression; cancer therapy; cell-ECM interaction; extracellular matrix; metastasis
    DOI:  https://doi.org/10.1515/mr-2021-0028
  3. Cell Chem Biol. 2023 Sep 21. pii: S2451-9456(23)00284-2. [Epub ahead of print]30(9): 1012-1014
    Glutamine availability unleashes dendritic cells' anti-tumor power.
    Mauro Corrado, Christian Frezza.
      Metabolic competition within the tumor microenvironment (TME) shapes the efficacy of anticancer immunity. In the August 3rd issue of Nature, Guo et al.1 show that glutamine is an intercellular metabolic checkpoint between cancer and immune cells. Targeting glutamine metabolism in the TME is a promising strategy to improve anti-cancer therapy.
    DOI:  https://doi.org/10.1016/j.chembiol.2023.08.012
  4. Med Rev (Berl). 2021 Dec;1(2): 222-243
    Tumor-associated macrophages, dendritic cells, and neutrophils: biological roles, crosstalk, and therapeutic relevance.
    Mingyi Shen, Yanhua Du, Youqiong Ye.
      Tumor-associated myeloid cells constitute a series of plastic and heterogeneous cell populations within the tumor microenvironment (TME), and exhibit different phenotypes and functions in response to various microenvironmental signals. In light of promising preclinical data indicating that myeloid-based therapy can effectively suppress tumor growth, a series of novel immune-based therapies and approaches are currently undergoing clinical evaluation. A better understanding of the diversity and functional roles of different myeloid cell subtypes and of how they are associated with TME remodeling may help to improve cancer therapy. Herein, we focus on myeloid cells and discuss how tumor cells can simultaneously reprogram these cells through tumor-derived factors and metabolites. In addition, we discuss the interactions between myeloid cells and other cells in the TME that have the potential to directly or indirectly regulate tumor initiation, invasion, or angiogenesis. We further discuss the current and future potential applications of myeloid cells in the development of focused therapeutic strategies in cancer treatment.
    Keywords:  cell-interaction; dendritic cells; macrophages; neutrophils; therapy; tumor microenvironment
    DOI:  https://doi.org/10.1515/mr-2021-0014
  5. Front Immunol. 2023 ;14 1213467
    Escherichia coli adhesion portion FimH polarizes M2 macrophages to M1 macrophages in tumor microenvironment via toll-like receptor 4.
    Wei Zhang, Li Xu, Xiaoyan Zhang, Jianqing Xu, Jun-O Jin.
       Background: Macrophages are key effector cells of innate immunity and play a critical role in the immune balance of disease pathogenesis, especially in the tumor microenvironment. In previous studies, we showed that FimH, an Escherichia coli adhesion portion, promoted dendritic cell activation. However, the effect of FimH in macrophage polarization has yet to be fully examined. In this study, we investigated the potential effect of FimH on macrophages, as well as the polarization from M2 to M1 macrophages, contributing to the overall antitumor effect.
    Methods: Mouse bone marrow derived macrophages and peritoneal macrophages were generated to test the effect of FimH in vitro. The expression of costimulatory molecules and production of cytokines were analyzed. The effect of FimH in the tumor-associated macrophages was examine in the B16F10-tumor bearing C57BL/6.
    Results: FimH was found to promote M1 macrophage activation. In addition, FimH polarized M2 macrophages, which were induced by interleukin (IL)-4 and IL-13 into M1 macrophages were dependent on toll-like receptor 4 and myeloid differentiation factor 2. Moreover, FimH reprogramed the tumor-associated macrophage (TAM) into M1 macrophages in B16 melanoma tumor-bearing mice and promoted an inflammatory reaction in the tumor microenvironment (TME). Furthermore, FimH promoted M1 macrophage activation, as well as the reversion of M2 macrophages into M1 macrophages in humans. Finally, FimH treatment was found to enhance the anti-cancer immunity of anti-PD-L1 antibody by the induction of M1 polarization from TAM.
    Conclusion: This study demonstrated the potential effect of FimH on the activation of macrophages, responsible for the repolarization of M2 macrophages into the M1 phenotype via the TLR4 signaling pathway. Moreover, FimH could also reprogram TAM polarization to the M1 status in the TME, as well as enhance the anti-tumor activity of immune checkpoint blockade.
    Keywords:  fimH; macrophage polarization; myeloid differentiation factor 2; toll-like receptor 4; tumor-associated macrophage
    DOI:  https://doi.org/10.3389/fimmu.2023.1213467
  6. Biochim Biophys Acta Rev Cancer. 2023 Sep 16. pii: S0304-419X(23)00133-6. [Epub ahead of print] 188984
    Dietary fat and lipid metabolism in the tumor microenvironment.
    Swagata Goswami, Qiming Zhang, Cigdem Elif Celik, Ethan M Reich, Ömer H Yilmaz.
      Metabolic reprogramming has been considered a core hallmark of cancer, in which excessive accumulation of lipids promote cancer initiation, progression and metastasis. Lipid metabolism is often considered as the digestion and absorption process of dietary fat, and the ways in which cancer cells utilize lipids are often influenced by the complex interactions within the tumor microenvironment. Among multiple cancer risk factors, obesity has a positive association with multiple cancer types, while diets like calorie restriction and fasting improve health and delay cancer. Impact of these diets on tumorigenesis or cancer prevention are generally studied on cancer cells, despite heterogeneity of the tumor microenvironment. Cancer cells regularly interact with these heterogeneous microenvironmental components, including immune and stromal cells, to promote cancer progression and metastasis, and there is an intricate metabolic crosstalk between these compartments. Here, we focus on discussing fat metabolism and response to dietary fat in the tumor microenvironment, focusing on both immune and stromal components and shedding light on therapeutic strategies surrounding lipid metabolic and signaling pathways.
    Keywords:  Fatty acid; High fat diet; Immunosuppression; Lipid metabolism; Obesity; Therapeutic intervention; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.bbcan.2023.188984
  7. Tuberc Respir Dis (Seoul). 2023 Sep 20.
    Immune evasion of G-CSF and GM-CSF in lung cancer.
    Yeonhee Park, Chauek Chung.
      Tumor immune evasion is a complex process that involves various mechanisms, such as antigen recognition restriction, immune system suppression, and T cell exhaustion. The tumor microenvironment contains various immune cells involved in immune evasion. Recent studies have demonstrated that granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) induce immune evasion in lung cancer by modulating neutrophils and myeloid-derived suppressor cells. Here we describe the origin and function of G-CSF and GM-CSF, particularly their role in immune evasion in lung cancer. In addition, their effects on programmed death-ligand 1 expression and clinical implications are discussed.
    Keywords:  G-CSF; GM-CSF; MDSC; PD-L1; immune evasion; neutrophils
    DOI:  https://doi.org/10.4046/trd.2023.0037
  8. Front Immunol. 2023 ;14 1238233
    The diversity and dynamics of tumor-associated macrophages in recurrent glioblastoma.
    Lingyun Zhang, Yu Jiang, Gao Zhang, Shiyou Wei.
      Despite tremendous efforts to exploit effective therapeutic strategies, most glioblastoma (GBM) inevitably relapse and become resistant to therapies, including radiotherapy and immunotherapy. The tumor microenvironment (TME) of recurrent GBM (rGBM) is highly immunosuppressive, dominated by tumor-associated macrophages (TAMs). TAMs consist of tissue-resident microglia and monocyte-derived macrophages (MDMs), which are essential for favoring tumor growth, invasion, angiogenesis, immune suppression, and therapeutic resistance; however, restricted by the absence of potent methods, the heterogeneity and plasticity of TAMs in rGBM remain incompletely investigated. Recent application of single-cell technologies, such as single-cell RNA-sequencing has enabled us to decipher the unforeseen diversity and dynamics of TAMs and to identify new subsets of TAMs which regulate anti-tumor immunity. Here, we first review hallmarks of the TME, progress and challenges of immunotherapy, and the biology of TAMs in the context of rGBM, including their origins, categories, and functions. Next, from a single-cell perspective, we highlight recent findings regarding the distinctions between tissue-resident microglia and MDMs, the identification and characterization of specific TAM subsets, and the dynamic alterations of TAMs during tumor progression and treatment. Last, we briefly discuss the potential of TAM-targeted strategies for combination immunotherapy in rGBM. We anticipate the comprehensive understanding of the diversity and dynamics of TAMs in rGBM will shed light on further improvement of immunotherapeutic efficacy in rGBM.
    Keywords:  immunotherapy; microglia; monocyte-derived macrophages; recurrent glioblastoma; single-cell; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2023.1238233
  9. Med Rev (Berl). 2021 Dec;1(2): 111-113
    Understanding metabolic reprogramming in tumor microenvironment.
    Shaokun Shu, Ying Xu, Qimin Zhan.
      
    DOI:  https://doi.org/10.1515/mr-2021-0037
  10. Cancer Discov. 2023 Sep 20.
    Formate supplementation enhances anti-tumor CD8+ T cell fitness and efficacy of PD-1 blockade.
    Jared H Rowe, Ilaria Elia, Osmaan Shahid, Emily F Gaudiano, Natalia E Sifnugel, Sheila Johnson, Amy G Reynolds, Megan E Fung, Shakchhi Joshi, Martin W LaFleur, Joon Seok Park, Kristen E Pauken, Joshua D Rabinowitz, Gordon J Freeman, Marcia C Haigis, Arlene H Sharpe.
      The tumor microenvironment (TME) restricts anti-tumor CD8+ T cell function and immunotherapy responses. Cancer cells compromise metabolic fitness of CD8+ T cells within the TME, but the mechanisms are largely unknown. Here we demonstrate one carbon (1C) metabolism is enhanced in T cells in an antigen-specific manner. Therapeutic supplementation of 1C metabolism using formate enhances CD8+ T cell fitness and anti-tumor efficacy of PD-1 blockade in B16-OVA tumors. Formate supplementation drives transcriptional alterations in CD8+ T cell metabolism and increases gene signatures for cellular proliferation and activation. Combined formate and anti-PD-1 therapy increases tumor-infiltrating CD8+ T cells, which are essential for the enhanced tumor control. Our data demonstrate formate provides metabolic support to CD8+ T cells reinvigorated by anti-PD-1 to overcome a metabolic vulnerability in 1C metabolism in the TME to further improve T cell function.
    DOI:  https://doi.org/10.1158/2159-8290.CD-22-1301
  11. Int J Biol Macromol. 2023 Sep 16. pii: S0141-8130(23)03809-6. [Epub ahead of print]253(Pt 3): 126912
    Efficient TNBC immunotherapy by dual reprogramming tumor-infiltrating dendritic cells and tumor-associated macrophages with stimulus-responsive miR155 nanocomplexes.
    Zhenghui Jing, Yanfeng Li, Jinxiao Song, Xinlong Zang.
      Triple negative breast cancer (TNBC) remains to be a formidable adversary with high mortality and unfavorable prognosis. Tumor microenvironment comprises of various constituents, among them, tumor infiltrating dendritic cells (TIDCs) and tumor-associated macrophages (TAMs) which have been recognized as pivotal factors responsible for mediating immune responses. Overcoming the refractory properties of TIDCs and TAMs is critical for inducing a robust and sustained immune response against cancer cells. In this study, pH/ROS-responsive microRNA-155 (miR155) nanocomplexes (MiR@PCPmP NPs) were developed to reprogram TIDCs and TAMs for efficient TNBC immunotherapy. This nanoplatform was based on a pH/ROS cleavable copolymer of poly(ethylene glycol)-carboxydimethyl maleate-poly(ethyleneimine)-peroxalate ester-poly(ε-caprolactone) grafted with mannose moieties (PEG-CDM-PEI[Man]-ox-PCL) which self-assembled with miRNA to form nanocomplexes. In the tumor microenvironment, the nanocomplexes showed selective cellular uptake by TIDCs and TAMs through PEG detachment and mannose exposure, followed by efficient endosomal escape, cytosolic miR155 release, and the dual-reprogramming of TIDCs and TAMs. Our results showed that MiR@PCPmP NPs significantly improved antitumor immune responses with highly infiltrating CD8+ T cells while restraining immunosuppressive components in 4T1 tumor-bearing mice. Furthermore, the nanoparticles effectively suppressed both primary tumors and pulmonary metastatic nodules without obvious systemic toxicity. This research highlights the potential of dual-reprogramming of TIDCs and TAMs with the miR155 nanocomplexes as a promising strategy for TNBC immunotherapy, with potential for translation to other cancers with a similar microenvironment.
    Keywords:  Nanocomplexes; TNBC; Tumor infiltrating dendritic cells; Tumor-associated macrophages; microRNA 155
    DOI:  https://doi.org/10.1016/j.ijbiomac.2023.126912
  12. Cancer Discov. 2023 Sep 22. OF1
    CD300ld on Neutrophils Drives Immune Suppression and Tumor Growth.
      CD300ld expression on PMN-MDSCs promotes an immune-suppressive tumor microenvironment and tumor progression.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2023-152
  13. Front Cell Infect Microbiol. 2023 ;13 1222265
    JunB: a paradigm for Jun family in immune response and cancer.
    Fu-Jia Ren, Xiao-Yu Cai, Yao Yao, Guo-Ying Fang.
      Jun B proto-oncogene (JunB) is a crucial member of dimeric activator protein-1 (AP-1) complex, which plays a significant role in various physiological processes, such as placental formation, cardiovascular development, myelopoiesis, angiogenesis, endochondral ossification and epidermis tissue homeostasis. Additionally, it has been reported that JunB has great regulatory functions in innate and adaptive immune responses by regulating the differentiation and cytokine secretion of immune cells including T cells, dendritic cells and macrophages, while also facilitating the effector of neutrophils and natural killer cells. Furthermore, a growing body of studies have shown that JunB is involved in tumorigenesis through regulating cell proliferation, differentiation, senescence and metastasis, particularly affecting the tumor microenvironment through transcriptional promotion or suppression of oncogenes in tumor cells or immune cells. This review summarizes the physiological function of JunB, its immune regulatory function, and its contribution to tumorigenesis, especially focusing on its regulatory mechanisms within tumor-associated immune processes.
    Keywords:  AP-1; JunB; immune response; tumor microenvironment; tumorigenesis
    DOI:  https://doi.org/10.3389/fcimb.2023.1222265
  14. Mol Med. 2023 Sep 22. 29(1): 129
    Interaction between N6-methyladenosine modification and the tumor microenvironment in colorectal cancer.
    Jiali Yao, Yeke Song, Xiaoping Yu, Zhijie Lin.
      The incidence and mortality of colorectal cancer (CRC) are rapidly increasing worldwide. Recently, there has been significant attention given to N6-methyladenosine (m6A), the most common mRNA modification, especially for its effects on CRC development. It is important to note that the progression of CRC would be greatly hindered without the tumor microenvironment (TME). The interaction between CRC cells and their surroundings can activate and influence complex signaling mechanisms of epigenetic changes to affect the survival of tumor cells with a malignant phenotype. Additionally, the TME is influenced by m6A regulatory factors, impacting the progression and prognosis of CRC. In this review, we describe the interactions and specific mechanisms between m6A modification and the metabolic, hypoxia, inflammatory, and immune microenvironments of CRC. Furthermore, we summarize the therapeutic role that m6A modification can play in the CRC microenvironment, and discuss the current status, limitations, and potential future directions in this field. This review aims to provide new insights into the molecular targets and theoretical foundations for the treatment of CRC.
    Keywords:  Colorectal cancer; Tumor microenvironment; m6A
    DOI:  https://doi.org/10.1186/s10020-023-00726-2
  15. Mol Ther. 2023 Sep 20. pii: S1525-0016(23)00497-5. [Epub ahead of print]
    Expressing CXCR4 in CAR-T cells Suppresses MDSCs Recruitment via STAT3/NF-κB/SDF-1α axis to enhance Anti-tumor Efficacy against Pancreatic Cancer.
    Sun Ruixin, Sun Yansha, Wu Chuanlong, Liu Yifan, Zhou Min, Dong Yiwei, Du Guoxiu, Luo Hong, Shi Bizhi, Jiang Hua, Li Zonghai.
      Claudin18.2 (CLDN18.2)-specific chimeric antigen receptor (CAR-T) cells displayed limited efficacy in CLDN18.2 positive pancreatic ductal adenocarcinoma (PDAC). Strategies are needed to improve the trafficking capacity of CLDN18.2-specific CAR-T cells. PDAC has a unique microenvironment that consists of abundant cancer- associated fibroblasts (CAFs), which could secrete stromal cell-derived factor 1α (SDF-1α), the ligand of CXCR4. Then we constructed and explored CLDN18.2-targeted CAR-T cells with CXCR4 co-expression in treating immunocompetent mouse models of PDAC. The results indicated that CXCR4 could promote the infiltration of CAR-T cells and enhance their efficacy in vivo. Mechanistically, the activation of signal transducer and activator of transcription 3(STAT3) signaling was impaired in CXCR4 CAR-T cells, thereof reduced the release of inflammatory factors, such as TNF-α, IL-6 and IL-17A. Then, the less release of inflammatory factors suppressed SDF-1α secretion in CAFs via NF-κB pathway. Therefore, the decreased secretion of SDF-1α in feedback decreased the migration of myeloid-derived suppressor cells (MDSCs) in tumor sites. Overall, our study demonstrated that CXCR4 CAR-T cells could traffic more into tumor sites and meanwhile suppress MDSCs migration via STAT3/NF-κB/SDF-1α axis, to obtained better efficacy in CLDN18.2 positive pancreatic cancer. Our findings provide a theoretical rationale for CXCR4 CAR-T cell therapy in PDAC.
    DOI:  https://doi.org/10.1016/j.ymthe.2023.09.010
  16. Nat Commun. 2023 09 19. 14(1): 5810
    The tumor microenvironment shows a hierarchy of cell-cell interactions dominated by fibroblasts.
    Shimrit Mayer, Tomer Milo, Achinoam Isaacson, Coral Halperin, Shoval Miyara, Yaniv Stein, Chen Lior, Meirav Pevsner-Fischer, Eldad Tzahor, Avi Mayo, Uri Alon, Ruth Scherz-Shouval.
      The tumor microenvironment (TME) is comprised of non-malignant cells that interact with each other and with cancer cells, critically impacting cancer biology. The TME is complex, and understanding it requires simplifying approaches. Here we provide an experimental-mathematical approach to decompose the TME into small circuits of interacting cell types. We find, using female breast cancer single-cell-RNA-sequencing data, a hierarchical network of interactions, with cancer-associated fibroblasts (CAFs) at the top secreting factors primarily to tumor-associated macrophages (TAMs). This network is composed of repeating circuit motifs. We isolate the strongest two-cell circuit motif by culturing fibroblasts and macrophages in-vitro, and analyze their dynamics and transcriptomes. This isolated circuit recapitulates the hierarchy of in-vivo interactions, and enables testing the effect of ligand-receptor interactions on cell dynamics and function, as we demonstrate by identifying a mediator of CAF-TAM interactions - RARRES2, and its receptor CMKLR1. Thus, the complexity of the TME may be simplified by identifying small circuits, facilitating the development of strategies to modulate the TME.
    DOI:  https://doi.org/10.1038/s41467-023-41518-w
  17. Curr Opin Biotechnol. 2023 Sep 13. pii: S0958-1669(23)00103-9. [Epub ahead of print]84 102993
    Tumor lipid metabolism: a mechanistic link between diet and cancer progression.
    Yu-Jin Jeong, Thomas J Rogers, Carolyn E Anderson, Evan C Lien.
      The potential for 'anti-cancer' diets to markedly alter cancer risk and prognosis has captured the imagination of patients, physicians, and researchers alike, but many of these dietary recommendations come from correlative studies that attribute certain diets to altered cancer risk. While provocative, little is known about the molecular mechanisms behind how these dietary interventions impact cancer progression. Within this context, however, changes in tumor lipid metabolism are emerging as a key contributor. In this review, we examine the current understanding of lipid metabolism in the tumor microenvironment (TME), suggesting how diet-induced changes in lipid composition may regulate tumor progression and therapeutic efficacy. By dissecting various cellular pathways involved in lipid metabolism, we highlight how diet modulates the balance between saturated and unsaturated fatty acid (FA) species in tumors to impact cancer cell and stromal cell function. Finally, we describe how current cancer therapies may synergize with diet to improve therapeutic efficacy.
    DOI:  https://doi.org/10.1016/j.copbio.2023.102993
  18. Cytokine Growth Factor Rev. 2023 Sep 15. pii: S1359-6101(23)00063-1. [Epub ahead of print]
    Extracellular vesicles in cancer: Shaping the intricate network of metabolic reprogramming and immune interactions in the tumor microenvironment.
    Elisa Giovannetti, Tian Li.
      
    DOI:  https://doi.org/10.1016/j.cytogfr.2023.09.001
  19. Free Radic Biol Med. 2023 Sep 16. pii: S0891-5849(23)00640-8. [Epub ahead of print]
    Extracellular pyruvate kinase M2 induces cell migration through p-Tyr42 RhoA-mediated superoxide generation and epithelial-mesenchymal transition.
    Amir Hamza, Jung Yoon Cho, Kim Cuong Cap, Abu Jubayer Hossain, Jae-Gyu Kim, Jae-Bong Park.
      In the tumor microenvironment (TME), communication between cancer cells and tumor-associated macrophages (TAMs) through secreted extracellular proteins promotes cancer progression. Here, we observed that co-culturing cancer cells (4T1) and macrophage cells (Raw264.7) significantly enhanced superoxide production in both cell types. Using MALDI-TOF, we identified PKM2 as a highly secreted protein by Raw264.7 cells and bone marrow-derived monocytes. The extracellular recombinant PKM2 protein not only enhanced cancer cell migration and invasion but also increased superoxide production. Additionally, PKM2 was found to associate with the cell surface, and its binding to integrin α5/β1 receptor was inhibited by antibodies specifically targeting it. Furthermore, we investigated downstream signaling pathways involved in PKM2-induced superoxide production. We found that knock-down of RhoA and p47phox using siRNAs effectively abolished superoxide generation in response to extracellular PKM2. Notably, extracellular PKM2 triggered the phosphorylation of p47phox at Ser345 residue and RhoA at Tyr42 residue (p-Tyr42 RhoA). Moreover, extracellular PKM2 exerted regulatory control over the expression of key epithelial-mesenchymal transition (EMT) markers, including ZEB1, Snail1, vimentin, and E-cadherin. Interestingly, p-Tyr42 RhoA translocated to the nucleus, where it bound to the ZEB1 promoter region. In light of these findings, we propose that extracellular PKM2 within the TME plays a critical role in tumorigenesis by promoting cancer cell migration and invasion through RhoA/p47phox signaling pathway.
    Keywords:  PKM2; TAM; TME; p-Tyr42 RhoA; p-p47phox
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.09.016
  20. Med Oncol. 2023 Sep 20. 40(10): 303
    Role of tissue markers associated with tumor microenvironment in the progression and immune suppression of oral squamous cell carcinoma.
    Suganya Ramalingam, Sivaramakrishnan Shantha, Susruthan Muralitharan, Uma Sudhakar, Harikrishnan Thamizhchelvan, Venkatachalam Deepa Parvathi.
      Head and neck cancers (HNC) continues to dominate major cancers contributing to  mortality worldwide. Squamous cell carcinoma is the major type of HNC. Oral Squamous Cell Carcinoma grouped under HNC is a malignant tumor occurring in the oral cavity. The primary risk factors of OSCC are tobacco, alcohol consumption, etc. This review focuses on modulations, mechanisms, growth and differentiation of oral squamous cell carcinoma. Cancer cell surrounds itself with a group of elements forming a favorable environment known as tumor microenvironment (TME). It consists of numerous cells which includes immune cells, blood cells and acellular components that are responsible for the progression, immunosuppression, metastasis and angiogenesis of cancer. This review highlights the most important tissue biomarkers (mTOR, CAF, FOXp3, CD163, CD33, CD34) that are associated with TME cells. mTOR remains as the primary regulator responsible in cancer and its importance towards immune-suppression is highlighted. Tumor-associated macrophages associated with cancer development and its relationship with immunomodulatory mechanism and Tregs, which are potential blockers of immune response and its mechanism and aberrations are discussed. Cancer-associated fibroblasts that are a part of TME and their role in evading the immune response and myeloid derived suppressor cells that have slight control over the immune response and their mechanism in the tumor progression is further explained. These markers have been emphasised as therapeutic targets and are currently in different stages of clinical trials.
    Keywords:  CD163; CD33; CD34; Cancer-associated fibroblasts (CAF); FOXp3; Oral squamous cell carcinoma (OSCC); Tumor microenvironment; mTOR
    DOI:  https://doi.org/10.1007/s12032-023-02169-5
  21. Int Rev Cell Mol Biol. 2023 ;pii: S1937-6448(23)00116-8. [Epub ahead of print]381 131-157
    Circulating tumor cells and host immunity: A tricky liaison.
    Elena Muraro, Giulia Brisotto.
      During their dissemination, circulating tumor cells (CTCs) steadily face the immune system, which is a key player in the whole metastatic cascade, from intravasation to the CTC colonization of distant sites. In this chapter, we will go through the description of immune cells involved in this controversial dialogue encompassing both the anti-tumor activity and the tumor-promoting and immunosuppressive function mediated by several circulating immune effectors as natural killer (NK) cells, CD4+ and CD8+ T lymphocytes, T helper 17, regulatory T cells, neutrophils, monocytes, macrophages, myeloid-derived suppressor cells, dendritic cells, and platelets. Then, we will report on the same interaction from the CTCs point of view, depicting the direct and indirect mechanisms of crosstalk with the above mentioned immune cells. Finally, we will report the recent literature evidence on the potential prognostic role of the integrated CTCs and immune cells monitoring in cancer patients management.
    Keywords:  Circulating tumor cells; Immune system; Macrophages; Natural killer (NK) cells; Neutrophils; Platelets; Regulatory T cells; T lymphocytes
    DOI:  https://doi.org/10.1016/bs.ircmb.2023.07.002
  22. Int J Gen Med. 2023 ;16 4121-4141
    Insight into the Progress in CAR-T Cell Therapy and Combination with Other Therapies for Glioblastoma.
    Tingyu Liang, Yixuan Song, Lingui Gu, Yu Wang, Wenbin Ma.
      Glioblastoma (GBM) is the most common malignant primary brain cancer in adults. It is always resistant to existing treatments, including surgical resection, postoperative radiotherapy, and chemotherapy, which leads to a dismal prognosis and a high relapse rate. Therefore, novel curative therapies are urgently needed for GBM. Chimeric antigen receptor T (CAR-T) cell therapy has significantly improved life expectancy for hematological malignancies patients, and thus it increases the interest in applying CAR-T cell therapy for solid tumors. In the recently published research, it is indicated that there are numerous obstacles to achieve clinical benefits for solid tumors, especially for GBM, because of GBM anatomical characteristics (the blood-brain barrier and suppressive tumor microenvironment) and the tumor heterogeneity. CAR-T cells are difficult to penetrate blood-brain barrier, and immunosuppressive tumor microenvironment (TME), which induces CAR-T cell exhaustion, impairs CAR-T cell therapy response. Moreover, under the pressure of CAR-T cell therapy, the tumor heterogeneity and tumor plasticity drive tumor evolution and therapy resistance, such as antigen escape. Nonetheless, scientists strive for strategies to overcome these hurdles, including novel CAR-T cell designs and regional delivery. For instance, the structure of multi-antigen-targeted CAR-T cells can enrich CAR-T accumulation in tumor TME and eliminate abundant tumor cells to avoid tumor antigen heterogeneity. Additionally, paired with an immune modifier and one or more stimulating domains, different generation of innovations in the structure and manufacturing of CAR-T cells have improved efficacy and persistence. While single CAR-T cell therapy receives limited clinical survival benefit. Compared with single CAR-T cell therapy, the combination therapies have supplemented the treatment paradigm. Combinatorial treatment methods consolidate the CAR-T cells efficacy by regulating the tumor microenvironment, optimizing the CAR structure, targeting the CAR-T cells to the tumor cells, reversing the tumor-immune escape mechanisms, and represent a promising avenue against GBM, based on multiple impressive research. Moreover, exciting results are also reported to be realized through combining effective therapies with CAR-T cells in preclinical and clinical trials samples, have aroused inspiration to explore the antitumor function of combination therapies. In summary, this study aims to summarize the limitation of CAR-T cell therapies and introduces novel strategies to enhance CAR-T cell function as well as prospect the potential of the therapeutic combination.
    Keywords:  CAR-T; GBM; novel strategies; therapeutic combination
    DOI:  https://doi.org/10.2147/IJGM.S418837
  23. Cell Commun Signal. 2023 Sep 21. 21(1): 252
    The role of bone marrow microenvironment (BMM) cells in acute myeloid leukemia (AML) progression: immune checkpoints, metabolic checkpoints, and signaling pathways.
    Maryam Bakhtiyari, Mahsa Liaghat, Fatemeh Aziziyan, Hooriyeh Shapourian, Sheida Yahyazadeh, Maedeh Alipour, Shaghayegh Shahveh, Fahimeh Maleki-Sheikhabadi, Hossein Halimi, Razieh Forghaniesfidvajani, Hamidreza Zalpoor, Mohsen Nabi-Afjadi, Majid Pornour.
      Acute myeloid leukemia (AML) comprises a multifarious and heterogeneous array of illnesses characterized by the anomalous proliferation of myeloid cells in the bone marrow microenvironment (BMM). The BMM plays a pivotal role in promoting AML progression, angiogenesis, and metastasis. The immune checkpoints (ICs) and metabolic processes are the key players in this process. In this review, we delineate the metabolic and immune checkpoint characteristics of the AML BMM, with a focus on the roles of BMM cells e.g. tumor-associated macrophages, natural killer cells, dendritic cells, metabolic profiles and related signaling pathways. We also discuss the signaling pathways stimulated in AML cells by BMM factors that lead to AML progression. We then delve into the roles of immune checkpoints in AML angiogenesis, metastasis, and cell proliferation, including co-stimulatory and inhibitory ICs. Lastly, we discuss the potential therapeutic approaches and future directions for AML treatment, emphasizing the potential of targeting metabolic and immune checkpoints in AML BMM as prognostic and therapeutic targets. In conclusion, the modulation of these processes through the use of directed drugs opens up new promising avenues in combating AML. Thereby, a comprehensive elucidation of the significance of these AML BMM cells' metabolic and immune checkpoints and signaling pathways on leukemic cells can be undertaken in the future investigations. Additionally, these checkpoints and cells should be considered plausible multi-targeted therapies for AML in combination with other conventional treatments in AML. Video Abstract.
    Keywords:  Acute myeloid leukemia; Angiogenesis; Bone marrow microenvironment; Cancer metabolism; Chemoresistance; Immune checkpoint; Metabolic checkpoint
    DOI:  https://doi.org/10.1186/s12964-023-01282-2
  24. Semin Cancer Biol. 2023 Sep 16. pii: S1044-579X(23)00124-4. [Epub ahead of print]96 5-10
    Targeting intratumoral hypoxia to enhance anti-tumor immunity.
    Gregg L Semenza.
      Cancers express a large battery of genes by which they establish an immunosuppressive tumor microenvironment. Many of these genes are induced by intratumoral hypoxia through transcriptional activation mediated by hypoxia-inducible factors HIF-1 and HIF-2. This review summarizes several recent reports describing hypoxia-induced mechanisms of immune evasion in sarcoma and breast, colorectal, hepatocellular, prostate and uterine cancer. These studies point to several novel therapeutic approaches to improve anti-tumor immunity and increase responses to immunotherapy.
    Keywords:  Hypoxia-inducible factor; Immune checkpoint inhibitor; Immune evasion; Immunotherapy; Intratumoral hypoxia
    DOI:  https://doi.org/10.1016/j.semcancer.2023.09.002
  25. Cancer Immunol Immunother. 2023 Sep 21.
    Metabolic diversity of tumor-infiltrating T cells as target for anti-immune therapeutics.
    Peipei Li, Fangchao Li, Yanfei Zhang, Xiaoyang Yu, Jingjing Li.
      Tumor-infiltrating T cells are promising drug targets to modulate the tumor microenvironment. However, tumor-infiltrating T lymphocytes, as central targets of cancer immunotherapy, show considerable heterogeneity and dynamics across tumor microenvironments and cancer types that may fundamentally influence cancer growth, metastasis, relapse, and response to clinical drugs. The T cell heterogeneity not only refers to the composition of subpopulations but also divergent metabolic states of T cells. Comparing to the diversity of tumor-infiltrating T cell compositions that have been well recognized, the metabolic diversity of T cells deserves more attention for precision immunotherapy. Single-cell sequencing technology enables panoramic stitching of the tumor bulk, partly by showing the metabolic-related gene expression profiles of tumor-infiltrating T cells at a single-cell resolution. Therefore, we here discuss T cell metabolism reprogramming triggered by tumor microenvironment as well as the potential application of metabolic targeting drugs. The tumor-infiltrating T cells metabolic pathway addictions among different cancer types are also addressed in this brief review.
    Keywords:  Cancer metabolism; Single-cell sequencing; T cell metabolism; Tumor microenvironment; Tumor-infiltrating T cell
    DOI:  https://doi.org/10.1007/s00262-023-03540-1
  26. Biomed Pharmacother. 2023 Sep 14. pii: S0753-3322(23)01312-4. [Epub ahead of print]167 115514
    Cancer cell-intrinsic PD-1: Its role in malignant progression and immunotherapy.
    Muhua Chen, Lei Bie, Jieer Ying.
      Programmed cell death protein-1 (PD-1), also called CD279, is coded by the PDCD1 gene and is constitutively expressed on the surface of immune cells. As a receptor and immune checkpoint, PD-1 can bind to programmed death ligand-1/programmed death ligand-2 (PD-L1/PD-L2) in tumor cells, leading to tumor immune evasion. Anti-PD-1 and anti-PD-L1 are important components in tumor immune therapy. PD-1 is also expressed as an intrinsic variant (iPD-1) in cancer cells where it plays important roles in malignant progression as proposed by recent studies. However, iPD-1 has received much less attention compared to PD-1 expressed on immune cells although there is an unmet medical need for fully elucidating the mechanisms of actions to achieve the best response in tumor immunotherapy. iPD-1 suppresses tumorigenesis in non-small cell lung cancer (NSCLC) and colon cancer, whereas it promotes tumorigenesis in melanoma, hepatocellular carcinoma (HCC), pancreatic ductal adenocarcinoma (PDAC), thyroid cancer (TC), glioblastoma (GBM), and triple-negative breast cancer (TNBC). In this review, we focus on the role of iPD-1 in tumorigenesis and development and its molecular mechanisms. We also deeply discuss nivolumab-based combined therapy in common tumor therapy. iPD-1 may explain the different therapeutic effects of anti-PD-1 treatment and provide critical information for use in combined anti-tumor approaches.
    Keywords:  Cancer cell-intrinsic PD-1; Combined therapy; Immunotherapy; Malignant progression; Tumor
    DOI:  https://doi.org/10.1016/j.biopha.2023.115514
  27. MedComm (2020). 2023 Oct;4(5): e350
    The role of platelets in the regulation of tumor growth and metastasis: the mechanisms and targeted therapy.
    Kaili Liao, Xue Zhang, Jie Liu, Feifei Teng, Yingcheng He, Jinting Cheng, Qijun Yang, Wenyige Zhang, Yuxuan Xie, Daixin Guo, Gaoquan Cao, Yanmei Xu, Bo Huang, Xiaozhong Wang.
      Platelets are a class of pluripotent cells that, in addition to hemostasis and maintaining vascular endothelial integrity, are also involved in tumor growth and distant metastasis. The tumor microenvironment is a complex and comprehensive system composed of tumor cells and their surrounding immune and inflammatory cells, tumor-related fibroblasts, nearby interstitial tissues, microvessels, and various cytokines and chemokines. As an important member of the tumor microenvironment, platelets can promote tumor invasion and metastasis through various mechanisms. Understanding the role of platelets in tumor metastasis is important for diagnosing the risk of metastasis and prolonging survival. In this study, we more fully elucidate the underlying mechanisms by which platelets promote tumor growth and metastasis by modulating processes, such as immune escape, angiogenesis, tumor cell homing, and tumor cell exudation, and further summarize the effects of platelet-tumor cell interactions in the tumor microenvironment and possible tumor treatment strategies based on platelet studies. Our summary will more comprehensively and clearly demonstrate the role of platelets in tumor metastasis, so as to help clinical judgment of the potential risk of metastasis in cancer patients, with a view to improving the prognosis of patients.
    Keywords:  mechanism research; platelets; targeted therapies; tumor growth; tumor metastasis
    DOI:  https://doi.org/10.1002/mco2.350
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