Targeting MDSCs and PD-L1 confers the therapeutic advantage of ablative hypofractionated radiotherapy over conventional fractionated radiotherapy

Publication date: Available online 12 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Jie Lan, Rui Li, Li-Mei Yin, Lei Deng, Jun Gui, Bao-Qing Chen, Lin Zhou, Mao-Bing Men, Qiao-Rong Huang, Xian-Ming Mo, Yu-Quan Wei, Bo Lu, Adam Dicker, Jian-Xin Xue, You Lu
PurposeAblative 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 ResultsWe 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. By altering immune regulation, AHFRT, but not CFRT, significantly delayed the growth of secondary tumors implanted outside the irradiation field.ConclusionTargeting 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.

Teaser

This study compared the immune alterations in response to ablative hypofractionated radiotherapy (AHFRT) and conventional fractionated radiotherapy (CFRT) under the same BED, and showed that AHFRT suppressed recruitment of MDSCs into tumors, releasing the inhibition on CD8⁺ T cells, and boosting not only local but also systemic anti-cancer immunity. Adding anti-PD-L1 immunotherapy further boosted the potency of AHFRT. This study extended the mechanisms underlying the efficacy of AHFRT and proposed strategy to combine radiotherapy with immunotherapy.


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