Fibroblast heterogeneity in tumor micro-environment: Role in immunosuppression and new therapies

Seminars in Immunology, Journal Year: 2020, Volume and Issue: 48, P. 101417 - 101417

Published: April 1, 2020

In tumors, Cancer-Associated Fibroblasts (CAFs) constitute the most prominent component of tumor microenvironment (TME). CAFs are heterogeneous and composed different CAF subsets exerting distinct functions in tumors. Specific subpopulations actively influence various aspects growth, including cancer cell survival proliferation, angiogenesis, extracellular matrix (ECM) remodeling, metastatic spread chemoresistance. During past decade, some have also been shown to modulate anti-tumor immune response. Indeed, they can increase content regulatory T lymphocytes inhibit activity effector cytotoxic cells. These mainly controlled by their constitutive secretion cytokines, chemokines, growth factors ECM proteins, either directly surrounding space or through micro-vesicles. Some express key regulators checkpoints. The roles played CAFs, both as immunosuppressor physical support for progression, set them promising targets therapies. this review, we describe main current knowledge on heterogeneity immunosuppressive microenvironment, well potential therapeutic implications.

Language: Английский

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Role of cancer‐associated fibroblast subpopulations in immune infiltration, as a new means of treatment in cancer

Immunological Reviews, Journal Year: 2021, Volume and Issue: 302(1), P. 259 - 272

Published: May 19, 2021

Abstract The tumor microenvironment (TME) has been identified as one of the driving factors progression and invasion. Within this microenvironment, cancer‐associated fibroblasts (CAF) have multiple tumor‐promoting functions play key roles in drug resistance, through mechanisms, including extracellular matrix (ECM) remodeling, production growth factors, cytokines, chemokines, modulation metabolism angiogenesis. More recently, a growing body evidence shown that CAF also modulate immune cell activity suppress anti‐tumor response. In review, we describe current knowledge on heterogeneity terms identity functions. Moreover, analyze how distinct subpopulations differentially interact with cells, particular focus T lymphocytes. We address specific subsets contribute to cancer induction an immunosuppressive microenvironment. Finally, highlight potential therapeutic strategies for targeting cancer.

Language: Английский

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Cancer‐associated fibroblasts: Key players in shaping the tumor immune microenvironment

Immunological Reviews, Journal Year: 2021, Volume and Issue: 302(1), P. 241 - 258

Published: June 1, 2021

Abstract Cancer immunotherapies have rapidly changed the therapeutic landscape for cancer. Nevertheless, most of patients show innate or acquired resistance to these therapies. Studies conducted in recent years highlighted an emerging role cancer‐associated fibroblasts (CAFs) immune regulation that shapes tumor microenvironment (TIME) and influences response cancer immunotherapies. In this review, we outline advances understanding phenotypic functional heterogeneity CAFs. We will focus on roles CAFs shaping TIME, especially under a framework immunity continuum, discuss current future CAF‐targeting strategies particular context optimizing success

Language: Английский

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Neoadjuvant therapy with immune checkpoint blockade, antiangiogenesis, and chemotherapy for locally advanced gastric cancer

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Jan. 3, 2023

Abstract Despite neoadjuvant/conversion chemotherapy, the prognosis of cT4a/bN+ gastric cancer is poor. Immune checkpoint inhibitors (ICIs) and antiangiogenic agents have shown activity in late-stage cancer, but their efficacy setting unclear. In this single-armed, phase II, exploratory trial (NCT03878472), we evaluate a combination ICI (camrelizumab), antiangiogenesis (apatinib), chemotherapy (S-1 ± oxaliplatin) for treatment cancer. The primary endpoints are pathological responses potential biomarkers. Secondary include safety, objective response, progression-free survival, overall survival. Complete major response rates 15.8% 26.3%. Pathological correlate significantly with microsatellite instability status, PD-L1 expression, tumor mutational burden. addition, multi-omics examination reveals several putative biomarkers responses, including RREB1 SSPO mutation, immune-related signatures, peripheral T cell expansion score. Multi-omics also demonstrates dynamic changes dominant subclones, immune microenvironments, receptor repertoires during neoadjuvant immunotherapy. toxicity post-surgery complications limited. These data support further validation ICI- antiangiogenesis-based therapy large randomized trials provide candidate

Language: Английский

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Reshaping the systemic tumor immune environment (STIE) and tumor immune microenvironment (TIME) to enhance immunotherapy efficacy in solid tumors

Journal of Hematology & Oncology, Journal Year: 2022, Volume and Issue: 15(1)

Published: July 7, 2022

The development of combination immunotherapy based on the mediation regulatory mechanisms tumor immune microenvironment (TIME) is promising. However, a deep understanding immunology must involve systemic environment (STIE) which was merely illustrated previously. Here, we aim to review recent advances in single-cell transcriptomics and spatial for studies STIE, TIME, their interactions, may reveal heterogeneity responses as well dynamic changes essential treatment effect. We evidence from preclinical clinical related significance overall survival, through different immunomodulatory pathways, such metabolic neuro-immunological pathways. also evaluate interactions after local radiotherapy or combined immunotherapy. focus our lung cancer, hepatocellular carcinoma, nasopharyngeal aiming reshape STIE TIME enhance efficacy.

Language: Английский

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Comprehensive characterization of the prostate tumor microenvironment identifies CXCR4/CXCL12 crosstalk as a novel antiangiogenic therapeutic target in prostate cancer

Molecular Cancer, Journal Year: 2022, Volume and Issue: 21(1)

Published: June 18, 2022

Abstract Background Crosstalk between neoplastic and stromal cells fosters prostate cancer (PCa) progression dissemination. Insight in cell-to-cell communication networks provides new therapeutic avenues to mold processes that contribute PCa tumor microenvironment (TME) alterations. Here we performed a detailed characterization of endothelial (TEC) delineate intercellular crosstalk TEC the TME. Methods isolated from 67 fresh radical prostatectomy (RP) specimens underwent multi-omic ex vivo as well orthogonal validation both functions key markers by immunohistochemistry (IHC) immunofluorescence (IF). To identify cell–cell interaction targets TEC, single-cell RNA sequencing (scRNA-seq) four patients who RP catalogue cellular TME composition. Targets were cross-validated using IHC, publicly available datasets, cell culture expriments xenograft mouse model. Results Compared adjacent normal (NEC) bulk RNA-seq analysis revealed upregulation genes associated with vasculature, collagen modification extracellular matrix remodeling TEC. PTGIR, PLAC9, CXCL12 VDR identified confirmed IF IHC an independent patient cohort. By scRNA-seq 27 (sub)types, including (EC) arterial, venous immature signatures, angiogenic tip EC. A focused molecular arterial displayed highest mRNA expression levels when compared all other (sub)populations showed negative prognostic role. Receptor-ligand predicted interactions derived its cognate receptor CXCR4 on was vitro validated actionable target highlighting vessel number- density- reducing activity CXCR4-inhibitor AMD3100 murine inhibition proliferation migration vitro. Conclusions Overall, our comprehensive novel highlights CXCR4/CXCL12 potential interfere angiogenesis PCa. Graphical

Language: Английский

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Current Landscape of Therapeutic Resistance in Lung Cancer and Promising Strategies to Overcome Resistance

Cancers, Journal Year: 2022, Volume and Issue: 14(19), P. 4562 - 4562

Published: Sept. 20, 2022

Lung cancer is one of the leading causes cancer-related deaths worldwide with a 5-year survival rate less than 18%. Current treatment modalities include surgery, chemotherapy, radiation therapy, targeted and immunotherapy. Despite advances in therapeutic options, resistance to therapy remains major obstacle effectiveness long-term treatment, eventually insensitivity, poor progression-free survival, disease relapse. Resistance mechanisms stem from genetic mutations and/or epigenetic changes, unregulated drug efflux, tumor hypoxia, alterations microenvironment, several other cellular molecular alterations. A better understanding these crucial for targeting factors involved resistance, establishing novel antitumor targets, developing strategies resensitize cells towards treatment. In this review, we summarize diverse driving radiotherapy, immunotherapy, promising help overcome resistance.

Language: Английский

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Cancer Resistance to Immunotherapy: Comprehensive Insights with Future Perspectives

Pharmaceutics, Journal Year: 2023, Volume and Issue: 15(4), P. 1143 - 1143

Published: April 4, 2023

Cancer immunotherapy is a type of treatment that harnesses the power immune systems patients to target cancer cells with better precision compared traditional chemotherapy. Several lines have been approved by US Food and Drug Administration (FDA) led remarkable success in solid tumors, such as melanoma small-cell lung cancer. These immunotherapies include checkpoint inhibitors, cytokines, vaccines, while chimeric antigen receptor (CAR) T-cell has shown responses hematological malignancies. Despite these breakthrough achievements, response variable among patients, only small percentage gained from this treatment, depending on histological tumor other host factors. develop mechanisms avoid interacting circumstances, which an adverse effect how effectively they react therapy. arise either due intrinsic factors within or microenvironment (TME). When scenario used therapeutic setting, term “resistance immunotherapy” applied; “primary resistance” denotes failure respond start, “secondary relapse following initial immunotherapy. Here, we provide thorough summary internal external underlying resistance Furthermore, variety are briefly discussed, along recent developments employed prevent relapses focus upcoming initiatives improve efficacy for patients.

Language: Английский

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Gut microbiome affects the response to immunotherapy in non‐small cell lung cancer

Thoracic Cancer, Journal Year: 2024, Volume and Issue: 15(14), P. 1149 - 1163

Published: April 4, 2024

Abstract Background Immunotherapy has revolutionized cancer treatment. Recent studies have suggested that the efficacy of immunotherapy can be further enhanced by influence gut microbiota. In this study, we aimed to investigate impact bacteria on effectiveness combining analysis clinical samples with validation in animal models. Methods order characterize diversity and composition microbiota its relationship response immune checkpoint inhibitors (ICIs), 16S ribosomal RNA (rRNA) GC–MS sequencing was performed 71 stool from patients advanced non‐small cell lung (NSCLC) prior treatment blockade (ICB). Furthermore, fecal transplantation (FMT) different into mice a subcutaneous tumor model established using Lewis line evaluate therapeutic effect PD‐1 varying Results The results demonstrated significant association between elevated ICIs, p < 0.05. Faecalibacterium markedly increased responders (R), accompanied short‐chain fatty acid (SCFA) levels, especially butanoic acid, acetic hexanoic Additionally, FMT R nonresponders (NR) could promote an anticancer reduce expression Ki‐67 cells tumors mice, Moreover, NR did not alter PD‐L1 tissues > consistently correlated optimistic prognosis NSCLC immunotherapy, which functionally mediated SCFAs. Conclusion findings present study indicated SCFAs is related immunotherapy. effectively delay progression, enhance thus providing evidence for improving patients.

Language: Английский

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IFNγ signaling integrity in colorectal cancer immunity and immunotherapy

Cellular and Molecular Immunology, Journal Year: 2021, Volume and Issue: 19(1), P. 23 - 32

Published: Aug. 12, 2021

Abstract The majority of colorectal cancer patients are not responsive to immune checkpoint blockade (ICB). interferon gamma (IFNγ) signaling pathway drives spontaneous and ICB-induced antitumor immunity. In this review, we summarize recent advances in the epigenetic, genetic, functional integrity IFNγ microenvironment its immunological relevance therapeutic efficacy resistance ICB. Moreover, discuss how target inform novel clinical trials treat with cancer.

Language: Английский

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