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Optimized CAR-T therapy based on spatiotemporal changes and chemotactic mechanisms of MDSCs induced by hypofractionated radiotherapy

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机构： [1]Division of Thoracic Tumor Multimodality Treatment, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China. [2]Department of Radiation Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China. [3]Clinical Trial Center, West China Hospital, Sichuan University, Chengdu 610041, China. [4]Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China. [5]Institute of Respiratory Health, Frontiers Science Center for Disease-Related Molecular Network, and Precision Medicine Research Center, Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu 610041, China. [6]Department of Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China

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Poor intratumoral infiltration is the major challenge for chimeric antigen receptor (CAR)-T cell therapy in solid tumors. Hypofractionated radiotherapy (HFRT) has been reported to induce immune cell infiltration and reshape the tumor immune microenvironment. Here, we showed that HFRT (5 × 5 Gy) mediated an early accumulation of intratumoral myeloid-derived suppressor cells (MDSCs) and decreased infiltration of T cells in the tumor microenvironment (TME) of immunocompetent mice bearing triple-negative breast cancer (TNBC) or colon cancer, which was further confirmed in tumors from patients. RNA sequencing (RNA-seq) and cytokine profiling analysis revealed that HFRT induced the activation and proliferation of tumor-infiltrated MDSCs, which was mediated by the interactions of multiple chemokines and chemokine receptors. Further investigation showed that when combined with HFRT, CXCR2 blockade significantly inhibited MDSCs trafficking to tumors and effectively enhanced the intratumoral infiltration and treatment efficacy of CAR-T cells. Our study demonstrates that MDSCs blockade combined with HFRT is promising for CAR-T cell therapy optimization in solid tumors.Copyright © 2023 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

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出版当年[2023]版：

大类 | 1 区

医学

小类 | 1 区生物工程与应用微生物 1 区遗传学 1 区医学：研究与实验

最新[2023]版：

大类 | 1 区

医学

小类 | 1 区生物工程与应用微生物 1 区遗传学 1 区医学：研究与实验

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第一作者机构： [1]Division of Thoracic Tumor Multimodality Treatment, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.

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通讯机构： [1]Division of Thoracic Tumor Multimodality Treatment, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China. [*1]Division of Thoracic Tumor Multimodality Treatment, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China

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