bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2023–09–17
twenty-two papers selected by
Peio Azcoaga, Biodonostia HRI
  1. Multifaceted collagen-DDR1 signaling in cancer.
  2. Editorial: Modulation of T-cell function and survival by the tumor microenvironment.
  3. NETosis: Sculpting tumor metastasis and immunotherapy.
  4. The Role of Stroma in Cancer Metabolism.
  5. CD39 (ENTPD1) in tumors: a potential therapeutic target and prognostic biomarker.
  6. Tumor microenvironmental nutrients, cellular responses, and cancer.
  7. Role of Human Monocarboxylate Transporter 1 (hMCT1) and 4 (hMCT4) in Tumor Cells and the Tumor Microenvironment.
  8. Lipid metabolic reprogramming in tumor microenvironment: from mechanisms to therapeutics.
  9. Tumor microenvironment and CAR-T cell immunotherapy in B-cell lymphoma.
  10. A role for platelets in metabolic reprogramming of tumor-associated macrophages.
  11. Mechanical factors driving cancer progression.
  12. The Evolution of Tumor Microenvironment in Gliomas and Its Implication for Target Therapy.
  13. Cancer immunotherapies: advances and bottlenecks.
  14. Exosome-mediated metabolic reprogramming: Implications in esophageal carcinoma progression and tumor microenvironment remodeling.
  15. Hybrid computational modeling highlights reverse warburg effect in breast cancer-associated fibroblasts.
  16. AXL receptor tyrosine kinase inhibition improves the anti-tumor effects of CD8+ T cells by inducing CD103+ dendritic cell-mediated T cell priming.
  17. Enhancing personalized immune checkpoint therapy by immune archetyping and pharmacological targeting.
  18. Siglec-9+ tumor-associated macrophages delineate an immunosuppressive subset with therapeutic vulnerability in patients with high-grade serous ovarian cancer.
  19. Manipulating the gut and tumor microbiota for immune checkpoint inhibitor therapy: from dream to reality.
  20. Combination of PARP inhibitor and CDK4/6 inhibitor modulates cGAS/STING-dependent therapy-induced senescence and provides "one-two punch" opportunity with anti-PD-L1 therapy in colorectal cancer.
  21. Stressed target cancer cells drive nongenetic reprogramming of CAR T cells and solid tumor microenvironment.
  22. Targeting innate immune pathways for cancer immunotherapy.
  1. Trends Cell Biol. 2023 Sep 12. pii: S0962-8924(23)00167-8. [Epub ahead of print]
    Multifaceted collagen-DDR1 signaling in cancer.
    Hua Su, Michael Karin.
      In addition to immune cells and fibroblasts, the tumor microenvironment (TME) comprises an extracellular matrix (ECM) which contains collagens (COLs) whose architecture and remodeling dictate cancer development and progression. COL receptors expressed by cancer cells sense signals generated by microenvironmental alterations in COL state to regulate cell behavior and metabolism. Discoidin domain receptor 1 (DDR1) is a key sensor of COL fiber state and composition that controls tumor cell metabolism and growth, response to therapy, and patient survival. This review focuses on DDR1 to NRF2 signaling, its modulation of autophagy and macropinocytosis (MP), and its role in cancer and other diseases. Elucidating the regulation of DDR1 activity and expression under different pathophysiological conditions will facilitate the discovery of new therapeutics.
    Keywords:  DDR1; autophagy; cancer; collagen; collagen receptors; macropinocytosis
    DOI:  https://doi.org/10.1016/j.tcb.2023.08.003
  2. Front Cell Dev Biol. 2023 ;11 1271772
    Editorial: Modulation of T-cell function and survival by the tumor microenvironment.
    Kristian M Hargadon, Courtney M Lappas, Shahrzad Jalali.
      
    Keywords:  T cell; cancer; immune regulation; tumor immunity; tumor microenvironment
    DOI:  https://doi.org/10.3389/fcell.2023.1271772
  3. Immunol Rev. 2023 Sep 15.
    NETosis: Sculpting tumor metastasis and immunotherapy.
    Yanyan Hu, Houhong Wang, Yang Liu.
      The process of neutrophil extracellular traps (NETs) formation, called NETosis, is a peculiar death modality of neutrophils, which was first observed as an immune response against bacterial infection. However, recent work has revealed the unique biology of NETosis in facilitating tumor metastatic process. Neutrophil extracellular traps released by the tumor microenvironment (TME) shield tumor cells from cytotoxic immunity, leading to impaired tumor clearance. Besides, tumor cells tapped by NETs enable to travel through vessels and subsequently seed distant organs. Targeted ablation of NETosis has been proven to be beneficial in potentiating the efficacy of cancer immunotherapy in the metastatic settings. This review outlines the impact of NETosis at almost all stages of tumor metastasis. Furthermore, understanding the multifaceted interplay between NETosis and the TME components is crucial for supporting the rational development of highly effective combination immunotherapeutic strategies with anti-NETosis for patients with metastatic disease.
    Keywords:  NETosis; immunotherapy; metastasis; neutrophil extracellular traps; tumor microenvironment
    DOI:  https://doi.org/10.1111/imr.13277
  4. Cold Spring Harb Perspect Med. 2023 Sep 11. pii: a041540. [Epub ahead of print]
    The Role of Stroma in Cancer Metabolism.
    Alec C Kimmelman, Mara H Sherman.
      The altered metabolism of tumor cells is a well-known hallmark of cancer and is driven by multiple factors such as mutations in oncogenes and tumor suppressor genes, the origin of the tissue where the tumor arises, and the microenvironment of the tumor. These metabolic changes support the growth of cancer cells by providing energy and the necessary building blocks to sustain proliferation. Targeting these metabolic alterations therapeutically is a potential strategy to treat cancer, but it is challenging due to the metabolic plasticity of tumors. Cancer cells have developed ways to scavenge nutrients through autophagy and macropinocytosis and can also form metabolic networks with stromal cells in the tumor microenvironment. Understanding the role of the tumor microenvironment in tumor metabolism is crucial for effective therapeutic targeting. This review will discuss tumor metabolism and the contribution of the stroma in supporting tumor growth through metabolic interactions.
    DOI:  https://doi.org/10.1101/cshperspect.a041540
  5. Biomark Med. 2023 Sep 15.
    CD39 (ENTPD1) in tumors: a potential therapeutic target and prognostic biomarker.
    Cuicui Li, Litian Zhang, Qiqi Jin, Haoyun Jiang, Chongyang Wu.
      As a regulator of the dynamic balance between immune-activated extracellular ATP and immunosuppressive adenosine, CD39 ectonucleotidase impairs the ability of immune cells to exert anticancer immunity and plays an important role in the immune escape of tumor cells within the tumor microenvironment. In addition, CD39 has been studied in cancer patients to evaluate the prognosis, the efficacy of immunotherapy (e.g., PD-1 blockade) and the prediction of recurrence. This article reviews the importance of CD39 in tumor immunology, summarizes the preclinical evidence on targeting CD39 to treat tumors and focuses on the potential of CD39 as a biomarker to evaluate the prognosis and the response to immune checkpoint inhibitors in tumors.
    Keywords:  CD39; CD8+ TIL; PD-1; adenosine; biomarker; exhaustion; immunosuppression; tumor microenvironment
    DOI:  https://doi.org/10.2217/bmm-2023-0202
  6. Cell Chem Biol. 2023 Sep 01. pii: S2451-9456(23)00281-7. [Epub ahead of print]
    Tumor microenvironmental nutrients, cellular responses, and cancer.
    Graham P Lobel, Yanqing Jiang, M Celeste Simon.
      Over the last two decades, the rapidly expanding field of tumor metabolism has enhanced our knowledge of the impact of nutrient availability on metabolic reprogramming in cancer. Apart from established roles in cancer cells themselves, various nutrients, metabolic enzymes, and stress responses are key to the activities of tumor microenvironmental immune, fibroblastic, endothelial, and other cell types that support malignant transformation. In this article, we review our current understanding of how nutrient availability affects metabolic pathways and responses in both cancer and "stromal" cells, by dissecting major examples and their regulation of cellular activity. Understanding the relationship of nutrient availability to cellular behaviors in the tumor ecosystem will broaden the horizon of exploiting novel therapeutic vulnerabilities in cancer.
    Keywords:  Cancer metabolism; cancer therapeutics; cancer-associated fibroblasts; immune cell metabolism; nutrient exchange; stress responses; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.chembiol.2023.08.011
  7. Cancer Manag Res. 2023 ;15 957-975
    Role of Human Monocarboxylate Transporter 1 (hMCT1) and 4 (hMCT4) in Tumor Cells and the Tumor Microenvironment.
    Tian Liu, Shangcong Han, Yu Yao, Guiming Zhang.
      In recent years, the abnormal glucose metabolism of tumor cells has attracted increasing attention. Abnormal glucose metabolism is closely related to the occurrence and development of tumors. Monocarboxylate transporters (MCTs) transport the sugar metabolites lactic acid and pyruvate, which affect glucose metabolism and tumor progression in a variety of ways. Thus, research has recently focused on MCTs and their potential functions in cancer. The MCT superfamily consists of 14 members. MCT1 and MCT4 play a crucial role in the maintenance of intracellular pH in tumor cells by transporting monocarboxylic acids (such as lactate, pyruvate and butyrate). MCT1 and MCT4 are highly expressed in a variety of tumor cells and are involved the proliferation, invasion and migration of tumor cells, which are closely related to the prognosis of cancer. Because of their important functions in tumor cells, MCT1 and MCT4 have become potential targets for cancer treatment. In this review, we focus on the structure, function and regulation of MCT1 and MCT4 and discuss the developed inhibitors of MCT1 and MCT4 to provide more comprehensive information that might aid in the development of strategies targeting MCTs in cancer.
    Keywords:  function; monocarboxylate transporter; regulation; tumor; tumor microenvironment
    DOI:  https://doi.org/10.2147/CMAR.S421771
  8. J Hematol Oncol. 2023 Sep 12. 16(1): 103
    Lipid metabolic reprogramming in tumor microenvironment: from mechanisms to therapeutics.
    Hao-Ran Jin, Jin Wang, Zi-Jing Wang, Ming-Jia Xi, Bi-Han Xia, Kai Deng, Jin-Lin Yang.
      Lipid metabolic reprogramming is an emerging hallmark of cancer. In order to sustain uncontrolled proliferation and survive in unfavorable environments that lack oxygen and nutrients, tumor cells undergo metabolic transformations to exploit various ways of acquiring lipid and increasing lipid oxidation. In addition, stromal cells and immune cells in the tumor microenvironment also undergo lipid metabolic reprogramming, which further affects tumor functional phenotypes and immune responses. Given that lipid metabolism plays a critical role in supporting cancer progression and remodeling the tumor microenvironment, targeting the lipid metabolism pathway could provide a novel approach to cancer treatment. This review seeks to: (1) clarify the overall landscape and mechanisms of lipid metabolic reprogramming in cancer, (2) summarize the lipid metabolic landscapes within stromal cells and immune cells in the tumor microenvironment, and clarify their roles in tumor progression, and (3) summarize potential therapeutic targets for lipid metabolism, and highlight the potential for combining such approaches with other anti-tumor therapies to provide new therapeutic opportunities for cancer patients.
    Keywords:  Cancer progression; Immune response; Lipid metabolism; Targeted therapy; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s13045-023-01498-2
  9. Eur J Haematol. 2023 Sep 14.
    Tumor microenvironment and CAR-T cell immunotherapy in B-cell lymphoma.
    Fengqing Cai, Junfeng Zhang, Hui Gao, Hongqiang Shen.
      Chimeric receptor antigen T cell (CAR-T cell) therapy has demonstrated effectiveness and therapeutic potential in the immunotherapy of hematological malignancies, representing a promising breakthrough in cancer treatment. Despite the efficacy of CAR-T cell therapy in B-cell lymphoma, response variability, resistance, and side effects remain persistent challenges. The tumor microenvironment (TME) plays an intricate role in CAR-T cell therapy of B-cell lymphoma. The TME is a complex and dynamic environment that includes various cell types, cytokines, and extracellular matrix components, all of which can influence CAR-T cell function and behavior. This review discusses the design principles of CAR-T cells, TME in B-cell lymphoma, and the mechanisms by which TME influences CAR-T cell function. We discuss emerging strategies aimed at modulating the TME, targeting immunosuppressive cells, overcoming inhibitory signaling, and improving CAR-T cell infiltration and persistence. Therefore, these processes enhance the efficacy of CAR-T cell therapy and improve patient outcomes in B-cell lymphoma. Further research will be needed to investigate the molecular and cellular events that occur post-infusion, including changes in TME composition, immune cell interactions, cytokine signaling, and potential resistance mechanisms. Understanding these processes will contribute to the development of more effective CAR-T cell therapies and strategies to mitigate treatment-related toxicities.
    Keywords:  B-cell lymphoma; CAR-T cell; resistance; strategies; tumor microenvironment (TME)
    DOI:  https://doi.org/10.1111/ejh.14103
  10. Front Physiol. 2023 ;14 1250982
    A role for platelets in metabolic reprogramming of tumor-associated macrophages.
    Ying Kang, Emmanuel Boadi Amoafo, Philomena Entsie, Gregory L Beatty, Elisabetta Liverani.
      Cancer incidence and mortality are growing worldwide. With a lack of optimal treatments across many cancer types, there is an unmet need for the development of novel treatment strategies for cancer. One approach is to leverage the immune system for its ability to survey for cancer cells. However, cancer cells evolve to evade immune surveillance by establishing a tumor microenvironment (TME) that is marked by remarkable immune suppression. Macrophages are a predominant immune cell within the TME and have a major role in regulating tumor growth. In the TME, macrophages undergo metabolic reprogramming and differentiate into tumor-associated macrophages (TAM), which typically assume an immunosuppressive phenotype supportive of tumor growth. However, the plasticity of macrophage biology offers the possibility that macrophages may be promising therapeutic targets. Among the many determinants in the TME that may shape TAM biology, platelets can also contribute to cancer growth and to maintaining immune suppression. Platelets communicate with immune cells including macrophages through the secretion of immune mediators and cell-cell interaction. In other diseases, altering platelet secretion and cell-cell communication has been shown to reprogram macrophages and ameliorate inflammation. Thus, intervening on platelet-macrophage biology may be a novel therapeutic strategy for cancer. This review discusses our current understanding of the interaction between platelets and macrophages in the TME and details possible strategies for reprogramming macrophages into an anti-tumor phenotype for suppressing tumor growth.
    Keywords:  cancer; metabolic reprogramming; platelet; tumor microenvironment; tumor-associated macrophages
    DOI:  https://doi.org/10.3389/fphys.2023.1250982
  11. Adv Cancer Res. 2023 ;pii: S0065-230X(23)00053-2. [Epub ahead of print]160 61-81
    Mechanical factors driving cancer progression.
    Jessanne Y Lichtenberg, Sydnie Tran, Priscilla Y Hwang.
      A fundamental step of tumor metastasis is tumor cell migration away from the primary tumor site. One mode of migration that is essential but still understudied is collective invasion, the process by which clusters of cells move in a coordinated fashion. In recent years, there has been growing interest to understand factors regulating collective invasion, with increasing number of studies investigating the biomechanical regulation of collective invasion. In this review we discuss the dynamic relationship between tumor microenvironment cues and cell response by first covering mechanical factors in the microenvironment and second, discussing the mechanosensing pathways utilized by cells in collective clusters to dynamically respond to mechanical matrix cues. Finally, we discuss model systems that have been developed which have increased our understanding of the mechanical factors contributing to tumor progression.
    Keywords:  Cancer associated fibroblasts; Collective invasion; Immune cells; Leader cells; Mechanical matrix cues; Mechanosensing; Tumor microenvironment
    DOI:  https://doi.org/10.1016/bs.acr.2023.06.002
  12. Int J Biol Sci. 2023 ;19(13): 4311-4326
    The Evolution of Tumor Microenvironment in Gliomas and Its Implication for Target Therapy.
    Yang Hu, Zhixing Li, Yichi Zhang, Yuzheng Wu, Zihao Liu, Jianhao Zeng, Zhexue Hao, Jin Li, Jiaoyan Ren, Maojin Yao.
      Gliomas develop in unique and complicated environments that nourish tumor cells. The tumor microenvironment (TME) of gliomas comprises heterogeneous cells, including brain-resident cells, immune cells, and vascular cells. Reciprocal interactions among these cells are involved in the evolution of the TME. Moreover, the study of attractive therapeutic strategies that target the TME is transitioning from basic research to the clinic. Mouse models are indispensable tools for dissecting the processes and mechanisms leading to TME evolution. In this review, we overview the paradoxical roles of the TME, as well as the recent progress of mouse models in TME research. Finally, we summarize recent advances in TME-targeting therapeutic strategies.
    Keywords:  Glioma; Mouse model; Targeted therapy; Tumor evolution; Tumor microenvironment
    DOI:  https://doi.org/10.7150/ijbs.83531
  13. Front Immunol. 2023 ;14 1212476
    Cancer immunotherapies: advances and bottlenecks.
    Rui Rui, Liqun Zhou, Shiming He.
      Immunotherapy has ushered in a new era in cancer treatment, and cancer immunotherapy continues to be rejuvenated. The clinical goal of cancer immunotherapy is to prime host immune system to provide passive or active immunity against malignant tumors. Tumor infiltrating leukocytes (TILs) play an immunomodulatory role in tumor microenvironment (TME) which is closely related to immune escape of tumor cells, thus influence tumor progress. Several cancer immunotherapies, include immune checkpoint inhibitors (ICIs), cancer vaccine, adoptive cell transfer (ACT), have shown great efficacy and promise. In this review, we will summarize the recent research advances in tumor immunotherapy, including the molecular mechanisms and clinical effects as well as limitations of immunotherapy.
    Keywords:  cancer immunotherapy; immune checkpoint blockade; neoadjuvant immunotherapy; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2023.1212476
  14. Cytokine Growth Factor Rev. 2023 Aug 30. pii: S1359-6101(23)00056-4. [Epub ahead of print]
    Exosome-mediated metabolic reprogramming: Implications in esophageal carcinoma progression and tumor microenvironment remodeling.
    Yong Xi, Yaxing Shen, Lijie Chen, Lijie Tan, Weiyu Shen, Xing Niu.
      Esophageal carcinoma is among the most fatal malignancies with increasing incidence globally. Tumor onset and progression can be driven by metabolic reprogramming, especially during esophageal carcinoma development. Exosomes, a subset of extracellular vesicles, display an average size of ∼100 nanometers, containing multifarious components (nucleic acids, proteins, lipids, etc.). An increasing number of studies have shown that exosomes are capable of transferring molecules with biological functions into recipient cells, which play crucial roles in esophageal carcinoma progression and tumor microenvironment that is a highly heterogeneous ecosystem through rewriting the metabolic processes in tumor cells and environmental stromal cells. The review introduces the reprogramming of glucose, lipid, amino acid, mitochondrial metabolism in esophageal carcinoma, and summarize current pharmaceutical agents targeting such aberrant metabolism rewiring. We also comprehensively overview the biogenesis and release of exosomes, and recent advances of exosomal cargoes and functions in esophageal carcinoma and their promising clinical application. Moreover, we discuss how exosomes trigger tumor growth, metastasis, drug resistance, and immunosuppression as well as tumor microenvironment remodeling through focusing on their capacity to transfer materials between cells or between cells and tissues and modulate metabolic reprogramming, thus providing a theoretical reference for the design potential pharmaceutical agents targeting these mechanisms. Altogether, our review attempts to fully understand the significance of exosome-based metabolic rewriting in esophageal carcinoma progression and remodeling of the tumor microenvironment, bringing novel insights into the prevention and treatment of esophageal carcinoma in the future.
    Keywords:  Esophageal carcinoma; Exosome; Lipid metabolism; Metabolic reprogramming; Tumor microenvironment; Tumor progression
    DOI:  https://doi.org/10.1016/j.cytogfr.2023.08.010
  15. Comput Struct Biotechnol J. 2023 ;21 4196-4206
    Hybrid computational modeling highlights reverse warburg effect in breast cancer-associated fibroblasts.
    Sahar Aghakhani, Sacha E Silva-Saffar, Sylvain Soliman, Anna Niarakis.
      Cancer-associated fibroblasts (CAFs) are amongst the key players of the tumor microenvironment (TME) and are involved in cancer initiation, progression, and resistance to therapy. They exhibit aggressive phenotypes affecting extracellular matrix remodeling, angiogenesis, immune system modulation, tumor growth, and proliferation. CAFs phenotypic changes appear to be associated with metabolic alterations, notably a reverse Warburg effect that may drive fibroblasts transformation. However, its precise molecular mechanisms and regulatory drivers are still under investigation. Deciphering the reverse Warburg effect in breast CAFs may contribute to a better understanding of the interplay between TME and tumor cells, leading to new treatment strategies. In this regard, dynamic modeling approaches able to span multiple biological layers are essential to capture the emergent properties of various biological entities when complex and intertwined pathways are involved. This work presents the first hybrid large-scale computational model for breast CAFs covering major cellular signaling, gene regulation, and metabolic processes. It was generated by combining a cell- and disease-specific asynchronous Boolean model with a generic core metabolic network leveraging both data-driven and manual curation approaches. This model reproduces the experimentally observed reverse Warburg effect in breast CAFs and further identifies Hypoxia-Inducible Factor 1 (HIF-1) as its key molecular driver. Targeting HIF-1 as part of a TME-centered therapeutic strategy may prove beneficial in the treatment of breast cancer by addressing the reverse Warburg effect. Such findings in CAFs, in light of our previously published results in rheumatoid arthritis synovial fibroblasts, point to a common HIF-1-driven metabolic reprogramming of fibroblasts in breast cancer and rheumatoid arthritis.
    Keywords:  Breast cancer; Cancer-associated fibroblasts; Hybrid modeling; Metabolic reprogramming
    DOI:  https://doi.org/10.1016/j.csbj.2023.08.015
  16. Biochem Biophys Res Commun. 2023 Sep 11. pii: S0006-291X(23)01051-3. [Epub ahead of print]680 7-14
    AXL receptor tyrosine kinase inhibition improves the anti-tumor effects of CD8+ T cells by inducing CD103+ dendritic cell-mediated T cell priming.
    Kyungtaek Im, Yun Jung Choi, Dong Ha Kim, Da-Som Kim, Kyosun Ban, Wonjun Ji, In-Jeoung Baek, Chang-Min Choi, Jae Cheol Lee, Jin Kyung Rho.
      AXL is a member of TAM receptor family and has been highlighted as a potential target for cancer treatment. Accumulating evidence has uncovered the critical role of the AXL signaling pathway in tumor growth, metastasis, and resistance against anti-cancer drugs, as well as its association with cancer immune escape. However, the function of AXL as a manipulator of the immune system in the tumor microenvironment (TME) remains unclear. Therefore, in this study, we investigated the impact of AXL on immune cells in the TME of a syngeneic tumor model using AXL knockout (AXL-/-) mice. Compared to AXL wild-type (AXL+/+) mice, tumor growth was significantly suppressed in AXL-/- mice, and an induced population of tumor-infiltrated CD8+ T cells and CD103+ dendritic cells (DCs) was observed. The change of CD8+ T cells and CD103+ DCs was also confirmed in tumor-draining lymph nodes (TdLN). In addition, the clonal expansion of OVA-specific CD8+ T cells was dominant in AXL-/- mice. Finally, anti-PD-1 treatment evidenced synergistic anti-cancer effects in AXL-/- mice. Overall, our data indicate that AXL signaling may inhibit the clonal expansion of tumor-specific CD8+ T cells through the regulation of the migration of CD8+ T cells and DCs in TME. Thus, AXL may be a powerful molecular target to improve anti-cancer effects through single or combined therapy with immune checkpoint inhibitors (ICI).
    Keywords:  AXL receptor tyrosine kinase (AXL); CD8(+) T cell; Dendritic cell (DC); Lung cancer; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.bbrc.2023.09.021
  17. Pharmacol Res. 2023 Sep 13. pii: S1043-6618(23)00270-0. [Epub ahead of print] 106914
    Enhancing personalized immune checkpoint therapy by immune archetyping and pharmacological targeting.
    Claudia Cerella, Mario Dicato, Marc Diederich.
      Immune checkpoint inhibitors (ICIs) are an expanding class of immunotherapeutic agents with the potential to cure cancer. Despite the outstanding clinical response in patient subsets, most individuals become refractory or develop resistance. Patient stratification and personalized immunotherapies are limited by the absence of predictive response markers. Recent findings show that dominant patterns of immune cell composition, T-cell status and heterogeneity, and spatiotemporal distribution of immune cells within the tumor microenvironment (TME) are becoming essential determinants of prognosis and therapeutic response. In this context, ICIs also function as investigational tools and proof of concept, allowing the validation of the identified mechanisms. After reviewing the current state of ICIs, this article will explore new comprehensive predictive markers for ICIs based on recent discoveries. We will discuss the recent establishment of a classification of TMEs into immune archetypes as a tool for personalized immune profiling, allowing patient stratification before ICI treatment. We will discuss the developing comprehension of T-cell diversity and its role in shaping the immune profile of patients. We describe the potential of strategies that score the mutual spatiotemporal modulation between T-cells and other cellular components of the TME. Additionally, we will provide an overview of a range of synthetic and naturally occurring or derived small molecules. We will compare compounds that were recently identified by in silico prediction to wet lab-validated drug candidates with the potential to function as ICIs and/or modulators of the cellular components of the TME.
    Keywords:  T-cells; cancer immunity; cell heterogeneity; immune checkpoints; predictive markers; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.phrs.2023.106914
  18. J Immunother Cancer. 2023 Sep;pii: e007099. [Epub ahead of print]11(9):
    Siglec-9+ tumor-associated macrophages delineate an immunosuppressive subset with therapeutic vulnerability in patients with high-grade serous ovarian cancer.
    Yiying Wang, Mengdi He, Chen Zhang, Kankan Cao, Guodong Zhang, Moran Yang, Yan Huang, Wei Jiang, Haiou Liu.
       BACKGROUND: The potent immunosuppressive properties of sialic acid-binding immunoglobulin-like lectin-9 (Siglec-9) on myeloid cells and lymphocytes provide a strong rationale for serving as a therapeutic target. However, the expression profile and critical role of Siglec-9 in high-grade serous ovarian cancer (HGSC) remain obscure. This study aimed to elucidate the prognostic significance of Siglec-9 expression and its predictive value for immunotherapy in HGSC.
    METHODS: Study enrolled two cohorts, consisting of 120 tumor microarray specimens of HGSC for immunohistochemistry (IHC) and 40 fresh tumor specimens for flow cytometry (FCM). Expression profile of Siglec-9 in immune cells was analyzed by both bioinformatics analysis and FCM. Role of Siglec-9 was studied to identify that Siglec-9+TAMs linked with an immunosuppressive phenotype by IHC and FCM, and block Siglec-9 was sensitive to immunotherapy by ex vivo and in vitro assays.
    RESULTS: Siglec-9 is predominantly expressed on tumor-associated macrophages (TAMs). High Siglec-9+TAMs were associated with inferior overall survival (OS). Both tumor-conditioned medium (TCM) and tumor ascites induced enrichment of Siglec-9+TAMs with protumorigenic phenotypes. Siglec-9+TAMs were associated with immunosuppressive tumor microenvironment (TME) characterized by exhausted CD8+T cells and increased immune checkpoint expression. Blockade of Siglec-9 suppressed phosphorylation of the inhibitory phosphatase SHP-1 and repolarized TAMs to antitumorigenic phenotype and retrieved cytotoxic activity of CD8+T cells in vitro and ex vivo. Responders toward antiprogrammed death receptor-1 (anti-PD-1) therapy present more Siglec-9+TAMs than non-responders. Furthermore, blockade Siglec-9 synergized with anti-PD-1 antibody to enhance the cytotoxic activity of CD8+T cells in tissues with higher Siglec-9+TAMs.
    CONCLUSIONS: Siglec-9+TAMs may serve as an independent prognostic of poor survival but a predictive biomarker for anti-PD-1/antiprogrammed death ligand-1 immunotherapy in HGSC. In addition, the potential of immunosuppressive Siglec-9+TAMs as a therapeutic target is worth further exploration.
    Keywords:  Immunotherapy; Tumor Escape; Tumor Microenvironment
    DOI:  https://doi.org/10.1136/jitc-2023-007099
  19. Trends Mol Med. 2023 Sep 11. pii: S1471-4914(23)00189-2. [Epub ahead of print]
    Manipulating the gut and tumor microbiota for immune checkpoint inhibitor therapy: from dream to reality.
    Nicolas Guillot, Barnabé Roméo, Shima Sepehri Manesh, Gerard Milano, Patrick Brest, Laurence Zitvogel, Paul Hofman, Baharia Mograbi.
      The past decade has witnessed a revolution in cancer treatment by shifting from conventional therapies to immune checkpoint inhibitors (ICIs). These immunotherapies unleash the host immune system against the tumor and have achieved unprecedented durable remission. However, 80% of patients do not respond. This review discusses how bacteria are unexpected drivers that reprogram tumor immunity. Manipulating the microbiota impacts on tumor development and reprograms the tumor microenvironment (TME) of mice on immunotherapy. We anticipate that harnessing commensals and the tumor microbiome holds promise to identify patients who will benefit from immunotherapy and guide the choice of new ICI combinations to advance treatment efficacy.
    Keywords:  antibiotics; commensal; fecal microbiota transplantation; immune checkpoint inhibitor therapy; predictive biomarker; probiotics; tumor microbiota
    DOI:  https://doi.org/10.1016/j.molmed.2023.08.004
  20. Cancer Sci. 2023 Sep 13.
    Combination of PARP inhibitor and CDK4/6 inhibitor modulates cGAS/STING-dependent therapy-induced senescence and provides "one-two punch" opportunity with anti-PD-L1 therapy in colorectal cancer.
    Tao Wang, Weizhen Liu, Qian Shen, Ruikang Tao, Chengguo Li, Qian Shen, Yao Lin, Yongzhou Huang, Lei Yang, Gengchen Xie, Jie Bai, Ruidong Li, Lulu Wang, Kaixiong Tao, Yuping Yin.
      Although PARP inhibitor (PARPi) has been proven to be a promising anticancer drug in cancer patients harboring BRCA1/2 mutation, it provides limited clinical benefit in colorectal cancer patients with a low prevalence of BRCA1/2 mutations. In our study, we found PARPi talazoparib significantly induced cellular senescence via inhibiting p53 ubiquitination and activating p21. Furthermore, CDK4/6i palbociclib amplified this therapy-induced senescence (TIS) in vitro and in vivo. Mechanistically, talazoparib and palbociclib combination induced senescence-associated secretory phenotype (SASP), and characterization of SASP components revealed type I interferon (IFN)-related mediators, which were amplified by cGAS/STING signaling. More importantly, RNA sequencing data indicated that combination therapy activated T cell signatures and combination treatment transformed the tumor microenvironment (TME) into a more antitumor state with increased CD8 T cells and natural killer (NK) cells and decreased macrophages and granulocytic myeloid-derived suppressor cells (G-MDSCs). Moreover, clearance of the TIS cells by αPD-L1 promoted survival in immunocompetent mouse colorectal cancer models. Collectively, we elucidated the synergistic antitumor and immunomodulatory mechanisms of the talazoparib-palbociclib combination. Further combination with PD-L1 antibody might be a promising "one-two punch" therapeutic strategy for colorectal cancer patients.
    Keywords:  cGAS/STING; colorectal cancer; immune checkpoint blockade; senotherapy; therapy-induced senescence
    DOI:  https://doi.org/10.1111/cas.15961
  21. Nat Commun. 2023 Sep 15. 14(1): 5727
    Stressed target cancer cells drive nongenetic reprogramming of CAR T cells and solid tumor microenvironment.
    Yufeng Wang, David L Drum, Ruochuan Sun, Yida Zhang, Feng Chen, Fengfei Sun, Emre Dal, Ling Yu, Jingyu Jia, Shahrzad Arya, Lin Jia, Song Fan, Steven J Isakoff, Allison M Kehlmann, Gianpietro Dotti, Fubao Liu, Hui Zheng, Cristina R Ferrone, Alphonse G Taghian, Albert B DeLeo, Marco Ventin, Giulia Cattaneo, Yongxiang Li, Youssef Jounaidi, Peigen Huang, Cristina Maccalli, Hanyu Zhang, Cheng Wang, Jibing Yang, Genevieve M Boland, Ruslan I Sadreyev, LaiPing Wong, Soldano Ferrone, Xinhui Wang.
      The poor efficacy of chimeric antigen receptor T-cell therapy (CAR T) for solid tumors is due to insufficient CAR T cell tumor infiltration, in vivo expansion, persistence, and effector function, as well as exhaustion, intrinsic target antigen heterogeneity or antigen loss of target cancer cells, and immunosuppressive tumor microenvironment (TME). Here we describe a broadly applicable nongenetic approach that simultaneously addresses the multiple challenges of CAR T as a therapy for solid tumors. The approach reprograms CAR T cells by exposing them to stressed target cancer cells which have been exposed to the cell stress inducer disulfiram (DSF) and copper (Cu)(DSF/Cu) plus ionizing irradiation (IR). The reprogrammed CAR T cells acquire early memory-like characteristics, potent cytotoxicity, enhanced in vivo expansion, persistence, and decreased exhaustion. Tumors stressed by DSF/Cu and IR also reprogram and reverse the immunosuppressive TME in humanized mice. The reprogrammed CAR T cells, derived from peripheral blood mononuclear cells of healthy donors or metastatic female breast cancer patients, induce robust, sustained memory and curative anti-solid tumor responses in multiple xenograft mouse models, establishing proof of concept for empowering CAR T by stressing tumor as a promising therapy for solid tumors.
    DOI:  https://doi.org/10.1038/s41467-023-41282-x
  22. Immunity. 2023 Sep 03. pii: S1074-7613(23)00331-X. [Epub ahead of print]
    Targeting innate immune pathways for cancer immunotherapy.
    Longyue L Cao, Jonathan C Kagan.
      The innate immune system is critical for inducing durable and protective T cell responses to infection and has been increasingly recognized as a target for cancer immunotherapy. In this review, we present a framework wherein distinct innate immune signaling pathways activate five key dendritic cell activities that are important for T cell-mediated immunity. We discuss molecular pathways that can agonize these activities and highlight that no single pathway can agonize all activities needed for durable immunity. The immunological distinctions between innate immunotherapy administration to the tumor microenvironment versus administration via vaccination are examined, with particular focus on the strategies that enhance dendritic cell migration, interferon expression, and interleukin-1 family cytokine production. In this context, we argue for the importance of appreciating necessity vs. sufficiency when considering the impact of innate immune signaling in inflammation and protective immunity and offer a conceptual guideline for the development of efficacious cancer immunotherapies.
    Keywords:  IL-1; STING; TLRs; Toll-like receptors; anti-tumor immunity; cGAS; cancer vaccines; dendritic cells; inflammasomes; innate immunity; pattern recognition receptors
    DOI:  https://doi.org/10.1016/j.immuni.2023.07.018
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