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

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 x 5 Gy) mediated an early accumulation of intratu-moral 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 re-ceptors. 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 promising for CAR-T cell therapy optimization in solid tumors.

Automated summary

HFRT can improve the major challenge of poor intratumoral infiltration in CAR-T cell therapy for solid tumors by inducing the activation and proliferation of MDSCs in the tumor microenvironment. Therefore, combining HFRT with MDSCs blockade can significantly enhance the intratumoral infiltration and treatment efficacy of CAR-T cells in solid tumor patients.