Division of Thoracic Tumor Multimodality Treatment, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
Department of Radiation Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China.
Mol Ther. 2023 Jul 5;31(7):2105-2119. doi: 10.1016/j.ymthe.2023.04.008. Epub 2023 Apr 17.
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.
肿瘤内浸润不良是嵌合抗原受体 (CAR)-T 细胞疗法在实体瘤中面临的主要挑战。分次短程放疗 (HFRT) 已被报道可诱导免疫细胞浸润并重塑肿瘤免疫微环境。在这里，我们发现 HFRT（5×5 Gy）介导了免疫功能正常的荷三阴性乳腺癌 (TNBC) 或结肠癌小鼠肿瘤内髓系来源抑制细胞 (MDSC) 的早期积累，并减少了肿瘤微环境 (TME) 中 T 细胞的浸润，这在患者的肿瘤中得到了进一步证实。RNA 测序 (RNA-seq) 和细胞因子谱分析显示，HFRT 通过多种趋化因子和趋化因子受体的相互作用诱导肿瘤浸润性 MDSC 的激活和增殖。进一步的研究表明，当与 HFRT 联合使用时，CXCR2 阻断显著抑制 MDSC 向肿瘤的迁移，并有效地增强了 CAR-T 细胞在肿瘤内的浸润和治疗效果。我们的研究表明，MDSC 阻断联合 HFRT 有望优化 CAR-T 细胞疗法在实体瘤中的应用。
