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Increasing evidence indicates that local hypofractionated radiotherapy (LRT) can elicit both immunogenic and immunosuppressive local and systemic immune responses. We thus hypothesized that blockade of LRT-induced immunosuppressive responses could augment the antitumor effects and induce an abscopal response. In this study, we found that the upregulation of Foxp3+ regulatory T cells (Tregs) in the mesothelioma tumor microenvironment after nonablative oligofractionated irradiation significantly limited the success of irradiation. Using DEREG mice, which allow conditional and efficient depletion of Foxp3+ Tregs by diphtheria toxin injection, we observed that transient Foxp3+ Treg depletion immediately after nonablative oligofractionated irradiation provided synergistic local control and biased the T cell repertoire toward central and effector memory T cells, resulting in long-term cure. Furthermore, this combination therapy showed significant abscopal effect on the nonirradiated tumors in a concomitant model of mesothelioma through systemic activation of cytotoxic T cells and enhanced production of IFN-γ and granzyme B. Although local control was preserved with one fraction of nonablative irradiation, three fractions were required to generate the abscopal effect. PD-1 and CTLA-4 were upregulated on tumor-infiltrating CD4+ and CD8+ T cells in irradiated and nonirradiated tumors, suggesting that immune checkpoint inhibitors could be beneficial after LRT and Foxp3+ Treg depletion. Our findings are applicable to the strategy of immuno-radiotherapy for generating optimal antitumor immune responses in the clinical setting. Targeting Tregs immediately after a short course of irradiation could have a major impact on the local response to irradiation and its abscopal effect.
Kohno et al. (Fri,) studied this question.