PI3Kδ /γinhibitor BR101801 extrinsically potentiates effector CD8 + T cell-dependent antitumor immunity and abscopal effect after local irradiation

Abstract

Background Radiotherapy enhances antitumor immunity. However, it also induces immunosuppressive responses, which are major hurdles for an effective treatment. Thus, targeting the immunosuppressive tumor microenvironment is essential for enhancing the antitumor immunity after radiotherapy. Retrospective studies show that a blockade of PI3Kδand/or 3, which are abundant in leukocytes, exhibits antitumor immune response by attenuating activity of immune suppressive cells, however, the single blockade of PI3Kδor γis not sufficient to completely eliminate solid tumor. Methods We used BR101801, PI3Kδ /γinhibitor in the CT-26 syngeneic mouse model with a subcutaneously implanted tumor. BR101801 was administered daily, and the target tumor site was locally irradiated. We monitored the tumor growth regularly and evaluated the immunological changes using flow cytometry, ELISpot, and transcriptional analysis. Results This study showed that BR101801 combined with irradiation promotes systemic antitumor immunity and abscopal response by attenuating the activity of immune suppressive cells in the CT-26 tumor model. BR101801 combined with irradiation systemically reduced the proliferation of regulatory T cells (Tregs) and enhanced the number of tumor-specific CD8α + T cells in the tumor microenvironment, thereby leading to tumor regression. Furthermore, the high ratio of CD8α + T cells to Tregs was maintained for 14 days after irradiation, resulting in remote tumor regression in metastatic lesions, the so-called abscopal effect. Moreover, our transcriptomic analysis showed that BR101801 combined with irradiation promoted the immune-stimulatory tumor microenvironment, suggesting that the combined therapy converts immunologically cold tumors into hot one. Conclusions Our data suggest the first evidence that PI3Kδ /γinhibition combined with irradiation promotes systemic antitumor immunity against solid tumors, providing the preclinical result of the potential use of PI3Kδ /γinhibitor as an immune-regulatory radiosensitizer.