Radiation Modulates Hepatic Siphoning of T Cells to Improve Immunotherapy Efficacy

Abstract

We sought to understand if and how liver metastases regulated systemic antitumor immunity.We conducted a multi-institutional evaluation the outcomes of patients with liver metastases (2000-2018). In total, 2100 patients with more than 10 solid cancer types were analyzed. Response rates and survival outcomes were assessed with Chi-squared, Kaplan-Meier, univariable/multivariable Cox regression and random forest machine learning analyses. Translational correlates were drawn from an institutional series of comprehensively sequenced patients. Preclinical evaluations were performed with murine syngeneic cancer models.We report that liver metastases diminish immunotherapy efficacy systemically in patients and preclinical models. Patients with liver metastases derive limited benefit from immunotherapy. In multiple mouse models, we show that liver metastases siphon activated CD8+ T cells from systemic circulation and create a systemic immune desert. In preclinical models, liver-directed radiotherapy eliminates immunosuppressive hepatic macrophages, increases hepatic T cell survival and reduces hepatic siphoning of T cells.Liver metastases co-opt host peripheral tolerance mechanisms to cause acquired immunotherapy resistance through CD8+ T cell deletion, and the combination of liver-directed radiotherapy and immunotherapy could promote systemic antitumor immunity.