A CCR5 antagonist enhances the radiosensitivity of hepatocarcinoma in a mouse model.

Abstract

Conventional fractionated radiotherapy (CFRT) for hepatocellular carcinoma (HCC) is limited by intrinsic radioresistance. In this study, we investigated the radiosensitizing potential of maraviroc, a chemokine receptor 5 (CCR5) antagonist, and its mechanistic basis in HCC. A murine HCC model was established by subcutaneous implantation of H22 cells into the hind limbs of mice. Tumor-bearing mice received CFRT with or without maraviroc, and tumor growth kinetics were evaluated. Systemic levels of myeloid-derived suppressor cells (MDSCs) in peripheral blood and plasma chemokine ligand 5 (CCL5) were longitudinally monitored post-irradiation. In vitro mechanistic studies utilized maraviroc combined with conditioned media from 2 Gy-irradiated H22 cells to dissect its radiosensitizing effects. H22 cell viability, proliferation and migration were assessed following irradiation with or without maraviroc. Flow cytometry was employed to quantify polymorphonuclear MDSC (PMN-MDSC) proliferation, differentiation and immunosuppressive capacity via T-cell proliferation assays. Compared to monotherapy with either CFRT or maraviroc alone, maraviroc combined with CFRT significantly inhibited HCC growth in the mouse model. In vitro, maraviroc did not directly enhance irradiation-induced H22 cell death or suppress proliferation but reversed PMN-MDSC-mediated immunosuppression by attenuating PMN-MDSC migration and abrogating PMN-MDSC suppression of T-cell proliferation. Maraviroc combined with CFRT significantly inhibited the differentiation of bone marrow cells into PMN-MDSCs. In conclusion, the synergistic application of CCR5 antagonist with CFRT significantly enhanced radiosensitivity in HCC, primarily through suppression of PMN-MDSCs differentiation and migration, coupled with blockade of their T-cell proliferation inhibitory functions.