Radiation-induced abscopal effect and its enhancement by programmed cell death 1 blockade in the hepatocellular carcinoma: A murine model study
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Background/Aims: The abscopal effect, a rare phenomenon induced by radiation, can be reinforced by immunotherapy. Although radiation therapy and immunotherapy are increasingly being utilized for the treatment of hepatocellular carcinoma (HCC), whether immunotherapy could boost the abscopal effect remains unclear. In this study, we aimed to elucidate the immunological mechanisms underlying the abscopal effect induced by the combination of irradiation and immunotherapy in a murine HCC model. Methods: A syngeneic HCC mouse model was established by transplanting murine Hepa 1–6 HCC cells into both hind legs of immunocompetent C57BL/6 mice. The tumors on the right hind legs were irradiated, and abscopal effects were observed in the non-irradiated tumors on the left hind leg with or without the coadministration of anti-programmed cell death 1 (PD-1) antibodies. Flow cytometric analyses were performed to analyze the distributions of immune cells infiltrating both irradiated and non-irradiated tumors and the tumor-draining lymph nodes (TDLNs). Results: Administration of 16 Gy in two fractions more effectively inhibited the growth of both irradiated and nonirradiated tumors with higher tumor infiltration of cytotoxic T cells than 8 Gy did in a single fraction. The higher dose also increased activated dendritic cells in TDLNs, which had higher expression of the programmed cell death ligand 1. Coadministration of anti-PD-1 antibodies significantly enhanced the abscopal effect and increased infiltration of activated cytotoxic T cells in both irradiated and non-irradiated tumors. Conclusions: Our findings show that adding anti-PD-1 therapy to radiation enhanced the abscopal effect in a syngeneic murine model of HCC.
Abstract
Background/Aims: The abscopal effect, a rare phenomenon induced by radiation, can be reinforced by immunotherapy. Although radiation therapy and immunotherapy are increasingly being utilized for the treatment of hepatocellular carcinoma (HCC), whether immunotherapy could boost the abscopal effect remains unclear. In this study, we aimed to elucidate the immunological mechanisms underlying the abscopal effect induced by the combination of irradiation and immunotherapy in a murine HCC model. Methods: A syngeneic HCC mouse model was established by transplanting murine Hepa 1–6 HCC cells into both hind legs of immunocompetent C57BL/6 mice. The tumors on the right hind legs were irradiated, and abscopal effects were observed in the non-irradiated tumors on the left hind leg with or without the coadministration of anti-programmed cell death 1 (PD-1) antibodies. Flow cytometric analyses were performed to analyze the distributions of immune cells infiltrating both irradiated and non-irradiated tumors and the tumor-draining lymph nodes (TDLNs). Results: Administration of 16 Gy in two fractions more effectively inhibited the growth of both irradiated and nonirradiated tumors with higher tumor infiltration of cytotoxic T cells than 8 Gy did in a single fraction. The higher dose also increased activated dendritic cells in TDLNs, which had higher expression of the programmed cell death ligand 1. Coadministration of anti-PD-1 antibodies significantly enhanced the abscopal effect and increased infiltration of activated cytotoxic T cells in both irradiated and non-irradiated tumors. Conclusions: Our findings show that adding anti-PD-1 therapy to radiation enhanced the abscopal effect in a syngeneic murine model of HCC.
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