Targeting MDSCs and PD-L 1 confers the therapeutic advantage of ablative hypofractionated radiotherapy over conventional fractionated radiotherapy

Purpose: Ablative hypofractionated radiotherapy (AHFRT) presents therapeutic advantage over conventional fractionated radiotherapy (CFRT) in primary and oligometastatic cancers, but the underlying mechanisms remain largely unknown. In this study, we compared the immune alterations in response to AHFRT vs. CFRT and examined the significance of immune regulations contributing to the efficacy of AHFRT. Experiment Design and Results: We established subcutaneous tumors using syngeneic lung cancer and melanoma cells in both immunocompetent and immunocompromised mice and treated them with AHFRT and CFRT under the same biological equivalent dose (BED). Compared to CFRT, AHFRT significantly inhibited tumor growth in immunocompetent, but not in immunocompromised mice. On the cellular level, AHFRT reduced the recruitment of myeloid-derived suppressor cells (MDSCs) into tumors, and decreased the expression of programmed death-ligand 1 (PD-L1) on those cells, which unlashed the cytotoxicity of CD8 + T cells. Through the down-regulation of vascular endothelial growth factor (VEGF), AHFRT inhibited VEGF/VEGFR signaling, which was essential for MDSC recruitment. When combined with anti-PD-L1 antibody, AHFRT presented a higher efficacy in controlling tumor growth and improving mouse survival. M AN US CR IP T AC CE PT ED ACCEPTED MANUSCRIPT 2 By altering immune regulation, AHFRT, but not CFRT, significantly delayed the growth of secondary tumors implanted outside the irradiation field. Conclusion: Targeting MDSC recruitment and enhancing anti-tumor immunity are crucial for the therapeutic efficacy of AHFRT. When combined with anti-PD-L1 immunotherapy, AHFRT is more potent for cancer treatment.