Suppressing MDSC Recruitment to the Tumor Microenvironment by Antagonizing CXCR2 to Enhance the Efficacy of Immunotherapy.
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ABSTRACT:
SUBMITTER: Bullock K
PROVIDER: S-EPMC8699249 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Cancer-associated fibroblasts (CAFs) suppress anti-tumor immunity mediated by T-lymphocytes – making CAFs tempting targets for enhancing cancer immunotherapy. Unfortunately, the signaling mechanisms driving CAF activity in tumors have crucial functions outside tumors. Consequently, agents like angiotensin receptor blockers (ARBs) that inhibit CAF activity are limited by systemic adverse effects such as hypotension. To address this challenge, we developed tumor microenvironment-activated ARBs (TMA-ARBs) by chemically linking ARBs to novel polymeric materials that selectively degrade in the tumor microenvironment. TMA-ARBs remain in an inactive, material-bound state until they reach tumors, wherein the ARBs become active as the materials break apart. This tumor-selective activity enhances the CAF-inhibiting effects of ARBs while eliminating blood pressure-lowering effects. By reducing CAF activity, TMA-ARBs induce a comprehensive immunostimulatory shift in the tumor microenvironment with improved T-lymphocyte activity and distribution. Accordingly, TMA-ARBs dramatically increase animal survival when combined with immunotherapy in mice with metastatic breast cancer.
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Project description:The development of combination immunotherapy based on the mediation of regulatory mechanisms of the tumor immune microenvironment (TIME) is promising. However, a deep understanding of tumor immunology must involve the systemic tumor immune environment (STIE) which was merely illustrated previously. Here, we aim to review recent advances in single-cell transcriptomics and spatial transcriptomics for the studies of STIE, TIME, and their interactions, which may reveal heterogeneity in immunotherapy responses as well as the dynamic changes essential for the treatment effect. We review the evidence from preclinical and clinical studies related to TIME, STIE, and their significance on overall survival, through different immunomodulatory pathways, such as metabolic and neuro-immunological pathways. We also evaluate the significance of the STIE, TIME, and their interactions as well as changes after local radiotherapy and systemic immunotherapy or combined immunotherapy. We focus our review on the evidence of lung cancer, hepatocellular carcinoma, and nasopharyngeal carcinoma, aiming to reshape STIE and TIME to enhance immunotherapy efficacy.
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