Metastasis is the primary cause of cancer mortality, and cancer frequently metastasizes to the liver. It is not clear whether liver immune tolerance mechanisms contribute to cancer outcomes. We report that liver metastases diminish immunotherapy efficacy systemically in patients and preclinical models. Patients with liver metastases derive limited benefit from immunotherapy independent of other established biomarkers of response. Consequently, liver metastases cre-ate a systemic immune desert in preclinical models. Similarly, patients with liver metastases have reduced peripheral T cell numbers and diminished tumoral T cell diversity and function. In preclinical models, liver-directed radiotherapy eliminates immunosuppressive hepatic macrophages, increases hepatic T cell survival and reduces hepatic siphoning of T cells. Thus, 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.
LI X, RAMADORI P, PFISTER D, SEEHAWER M, ZENDER L, HEIKENWALDER M. THE IMMUNOLOGICAL AND METABOLIC LANDSCAPE IN PRIMARY AND METASTATIC LIVER CANCER. NAT REV CANCER. 2021;21(9):541-557. DOI:10.1038/S41568-021-00383-9