PD-L1 Blockade Maintains Irradiation-Mediated Antitumor Immunity

High-dose ionizing irradiation (IR) is an effective method for directly inducing tumor cell death and tumor-specific adaptive immune responses, but local relapse frequently occurs because IR-induced antitumor immunity is not maintained. To gain insight into postirradiation immune responses responsible for the loss of antitumor immunity and acquired radioresistance, Deng and colleagues analyzed expression of programmed death-ligand (PD-L1), a negative regulator of effector T cells, in tumor xenografts following IR. PD-L1 was upregulated in irradiated tumors, suggesting that changes in the tumor immune microenvironment following irradiation restrict the function of infiltrating effector T cells. Alone, IR and anti–PD-L1 treatment each had minimal effects on tumor outgrowth; however, combining these therapies led to tumor regression and prevented growth of secondary tumors. Remarkably, mice treated with the combination therapy were also resistant to tumor rechallenge, signifying that combination therapy led to prolonged antitumor immunity. Synergism between IR and PD-L1 blockade was dependent on CD8⁺ T cells, as tumor growth was restored in CD8⁺ T cell-depleted, but not CD4⁺ T cell-depleted mice despite combination therapy. IR and anti–PD-L1 combination therapy led to a significant reduction in the number of myeloid-derived suppressor cells (MDSC) in tumor tissue, raising the possibility that CD8⁺ T cells might mediate antitumor immunity by limiting MDSC accumulation. Indeed, a coculture assay of activated CD8+ T cells and MDSCs from tumor-bearing mice revealed an increase in MDSC cell death, indicating that CD8+ T cells can directly mediate MDSC elimination. Collectively, these results suggest that irradiation-mediated antitumor immunity can be maintained when PD-L1 blockade restores CD8⁺ T-cell responses and reduces the number of MDSCs in tumor tissue and provide support for the use of IR and anti–PD-L1 combination therapy to reduce tumor relapses.

Deng L, Liang H, Burnette B, Beckett M, Darga T, Weichselbaum RR, et al. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest 2013 Jan 2 [Epub ahead of print].