Mechanisms regulating PD-L1 expression in cancers and associated opportunities for novel small-molecule therapeutics

Nature Reviews Clinical Oncology, Journal Year: 2022, Volume and Issue: 19(5), P. 287 - 305

Published: Feb. 7, 2022

Language: Английский

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Improvement of the anticancer efficacy of PD-1/PD-L1 blockade via combination therapy and PD-L1 regulation

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

Published: March 12, 2022

Abstract Immune checkpoint molecules are promising anticancer targets, among which therapeutic antibodies targeting the PD-1/PD-L1 pathway have been widely applied to cancer treatment in clinical practice and great potential. However, this is greatly limited by its low response rates certain cancers, lack of known biomarkers, immune-related toxicity, innate acquired drug resistance, etc. Overcoming these limitations would significantly expand applications blockade improve rate survival time patients. In present review, we first illustrate biological mechanisms immune checkpoints their role healthy system as well tumor microenvironment (TME). The inhibits effect T cells TME, turn regulates expression levels PD-1 PD-L1 through multiple mechanisms. Several strategies proposed solve anti-PD-1/PD-L1 treatment, including combination therapy with other standard treatments, such chemotherapy, radiotherapy, targeted therapy, anti-angiogenic immunotherapies even diet control. Downregulation TME via pharmacological or gene regulation methods improves efficacy treatment. Surprisingly, recent preclinical studies shown that upregulation also blockade. Immunotherapy a strategy provides novel insight into applications. This review aims guide development more effective less toxic immunotherapies.

Language: Английский

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Translational advances in pancreatic ductal adenocarcinoma therapy

Nature Cancer, Journal Year: 2022, Volume and Issue: 3(3), P. 272 - 286

Published: March 29, 2022

Language: Английский

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Define cancer-associated fibroblasts (CAFs) in the tumor microenvironment: new opportunities in cancer immunotherapy and advances in clinical trials

Molecular Cancer, Journal Year: 2023, Volume and Issue: 22(1)

Published: Oct. 2, 2023

Abstract Despite centuries since the discovery and study of cancer, cancer is still a lethal intractable health issue worldwide. Cancer-associated fibroblasts (CAFs) have gained much attention as pivotal component tumor microenvironment. The versatility sophisticated mechanisms CAFs in facilitating progression been elucidated extensively, including promoting angiogenesis metastasis, inducing drug resistance, reshaping extracellular matrix, developing an immunosuppressive Owing to their robust tumor-promoting function, are considered promising target for oncotherapy. However, highly heterogeneous group cells. Some subpopulations exert inhibitory role growth, which implies that CAF-targeting approaches must be more precise individualized. This review comprehensively summarize origin, phenotypical, functional heterogeneity CAFs. More importantly, we underscore advances strategies clinical trials CAF various cancers, also progressions immunotherapy.

Language: Английский

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Cancer-Associated Fibroblasts Suppress CD8+ T-cell Infiltration and Confer Resistance to Immune-Checkpoint Blockade

Cancer Research, Journal Year: 2022, Volume and Issue: 82(16), P. 2904 - 2917

Published: June 24, 2022

Abstract Immune-checkpoint blockade (ICB) promotes antitumor immune responses and can result in durable patient benefit. However, response rates breast cancer patients remain modest, stimulating efforts to discover novel treatment options. Cancer-associated fibroblasts (CAF) represent a major component of the tumor microenvironment have known immunosuppressive functions addition their well-established roles directly promoting growth metastasis. Here we utilized paired syngeneic mouse mammary carcinoma models show that CAF abundance is associated with insensitivity combination αCTLA4 αPD-L1 ICB. CAF-rich tumors exhibited an immunologically cold microenvironment, transcriptomic, flow cytometric, quantitative histopathologic analyses demonstrating relationship between density CD8+ T-cell–excluded phenotype. The receptor Endo180 (Mrc2) predominantly expressed on myofibroblastic CAFs, its genetic deletion depleted subset αSMA-expressing CAFs impaired progression vivo. wild-type, but not Endo180-deficient, coimplantation studies restricted T-cell intratumoral infiltration, knockout mice increased infiltration enhanced sensitivity ICB compared wild-type mice. Clinically, trial melanoma patients, high MRC2 mRNA levels were poor αPD-1 therapy, highlighting potential benefits therapeutically targeting specific subpopulation other cancers improve clinical immunotherapy. Significance: Paired help unravel interplay evasion, fibroblast subpopulations

Language: Английский

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IFNα Potentiates Anti–PD-1 Efficacy by Remodeling Glucose Metabolism in the Hepatocellular Carcinoma Microenvironment

Cancer Discovery, Journal Year: 2022, Volume and Issue: 12(7), P. 1718 - 1741

Published: April 12, 2022

The overall response rate for anti-PD-1 therapy remains modest in hepatocellular carcinoma (HCC). We found that a combination of IFNα and anti-PD-1-based immunotherapy resulted enhanced antitumor activity patients with unresectable HCC. In both immunocompetent orthotopic spontaneous HCC models, synergized the treatment led to significant enrichment cytotoxic CD27+CD8+ T cells. Mechanistically, suppressed HIF1α signaling by inhibiting FosB transcription cells, resulting reduced glucose consumption capacity consequentially establishing high-glucose microenvironment fostered T-cell costimulatory molecule Cd27 via mTOR-FOXM1 infiltrating CD8+ Together, these data reveal reprograms metabolism within tumor microenvironment, thereby liberating capacities potentiating PD-1 blockade-induced immune response. Our findings suggest cotreatment is an effective novel strategy HCC.Our study supports role IFNα-mediated immunity HCC, tumor-infiltrating cells may be promising biomarker stratifying therapy. See related commentary Kao et al., p. 1615. This article highlighted Issue feature, 1599.

Language: Английский

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Targeting signaling pathways in prostate cancer: mechanisms and clinical trials

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: June 24, 2022

Abstract Prostate cancer (PCa) affects millions of men globally. Due to advances in understanding genomic landscapes and biological functions, the treatment PCa continues improve. Recently, various new classes agents, which include next-generation androgen receptor (AR) signaling inhibitors (abiraterone, enzalutamide, apalutamide, darolutamide), bone-targeting agents (radium-223 chloride, zoledronic acid), poly(ADP-ribose) polymerase (PARP) (olaparib, rucaparib, talazoparib) have been developed treat PCa. Agents targeting other pathways, including cyclin-dependent kinase (CDK)4/6, Ak strain transforming (AKT), wingless-type protein (WNT), epigenetic marks, successively entered clinical trials. Furthermore, prostate-specific membrane antigen (PSMA) such as 177 Lu-PSMA-617 are promising theranostics that could improve both diagnostic accuracy therapeutic efficacy. Advanced studies with immune checkpoint (ICIs) shown limited benefits PCa, whereas subgroups mismatch repair (MMR) or CDK12 inactivation may benefit from ICIs treatment. In this review, we summarized targeted trials their underlying mechanisms, further discussed limitations future directions.

Language: Английский

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Roles of cancer-associated fibroblasts (CAFs) in anti- PD-1/PD-L1 immunotherapy for solid cancers

Molecular Cancer, Journal Year: 2023, Volume and Issue: 22(1)

Published: Feb. 10, 2023

Abstract In recent years, breakthroughs have been made in tumor immunotherapy. However, immunotherapy, particularly anti-PD-1/PD-L1 immune checkpoint inhibitors, is effective only a small percentage of patients solid cancer. How to improve the efficiency cancer immunotherapy an urgent problem be solved. As we all know, state microenvironment (TME) essential factor affecting effectiveness and cancer-associated fibroblasts (CAFs) TME attracted much attention years. one main components TME, CAFs interact with cells by secreting cytokines vesicles, participating ECM remodeling, finally response process. With in-depth study heterogeneity, new strategies are provided for finding targets combination predicting efficacy. this review, focus on role microenvironment, then further elaborate potential mechanisms pathways influencing addition, summarize clinical application value CAFs-related markers cancers.

Language: Английский

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Context-Specific Determinants of the Immunosuppressive Tumor Microenvironment in Pancreatic Cancer

Cancer Discovery, Journal Year: 2023, Volume and Issue: 13(2), P. 278 - 297

Published: Jan. 9, 2023

Immunotherapies have shown benefits across a range of human cancers, but not pancreatic ductal adenocarcinoma (PDAC). Recent evidence suggests that the immunosuppressive tumor microenvironment (TME) constitutes an important roadblock to their efficacy. The landscape TME differs substantially PDAC subtypes, indicating context-specific principles immunosuppression. In this review, we discuss how cells, local TME, and systemic host environmental factors drive immunosuppression in context. We argue unraveling mechanistic drivers modes will open new possibilities target more efficiently by using multimodal (immuno)therapeutic interventions. Immunosuppression is almost universal hallmark cancer, although entity highly heterogeneous its different subtypes phenotypes. Here, provide diverse cancer central executor various context-dependent immunosuppression, key challenges novel opportunities uncover, functionalize, functional nodes for therapeutic exploitation.

Language: Английский

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The hallmarks of cancer immune evasion

Cancer Cell, Journal Year: 2024, Volume and Issue: 42(11), P. 1825 - 1863

Published: Oct. 10, 2024

Language: Английский

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