Antiangiogenic Treatment Facilitates the Abscopal Effect of Radiation Therapy Combined With Anti-PD-1 in Hepatocellular Carcinoma

Abstract

IntroductionMetastasis is one of the most important factors contributing to poor prognosis in hepatocellular carcinoma (HCC). Radiotherapy (RT), along with its induced abscopal effect, is a promising treatment for metastatic patients. However, the incidence of abscopal effect in clinical practice is rare, even when RT is combined with immune checkpoint inhibitors (ICIs). In this study, we aim to investigate the role of antiangiogenic treatment on the abscopal effect induced by RT + ICIs. MethodsBilateral subcutaneous and orthotopic Hepa1-6 and Hep53.4 models were established and treated with different combination treatments. We evaluated changes in the immune microenvironment and vascular normalization by flow cytometry, TCR sequencing, chemotactic gene array, ELISA, and immunofluorescence. ResultsOur studies showed that antiangiogenic treatment with RT + ICIs increased the antitumor response of the unirradiated lesions. Mechanistically, blockade of vascular endothelial receptor 2 (Anti-VEGFR2) increased the activation and maturation of DCs and promoted the production CD8+ T cells in irradiated tumors. These CD8+ T cells were attracted by anti-VEGFR2-induced CCL5 secretion from M1 macrophages in unirradiated tumors. Besides that, Anti-VEGFR2 enhanced the function of CD8+ T cells by reducing myeloid-derived suppressor cells and regulatory T cells. ConclusionThis study demonstrated that the combination of antiangiogenic treatment with RT and ICIs enhanced the abscopal effects. The application of triple therapy and its induced abscopal effect may offer a novel therapeutic approach for HCC, particularly for cases with multiple metastatic lesions.