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In Nature medicine ; h5-index 170.0

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. In multiple mouse models, we show that liver metastases siphon activated CD8+ T cells from systemic circulation. Within the liver, activated antigen-specific Fas+CD8+ T cells undergo apoptosis following their interaction with FasL+CD11b+F4/80+ monocyte-derived macrophages. Consequently, liver metastases create 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.

Yu Jiali, Green Michael D, Li Shasha, Sun Yilun, Journey Sara N, Choi Jae Eun, Rizvi Syed Monem, Qin Angel, Waninger Jessica J, Lang Xueting, Chopra Zoey, El Naqa Issam, Zhou Jiajia, Bian Yingjie, Jiang Long, Tezel Alangoya, Skvarce Jeremy, Achar Rohan K, Sitto Merna, Rosen Benjamin S, Su Fengyun, Narayanan Sathiya P, Cao Xuhong, Wei Shuang, Szeliga Wojciech, Vatan Linda, Mayo Charles, Morgan Meredith A, Schonewolf Caitlin A, Cuneo Kyle, Kryczek Ilona, Ma Vincent T, Lao Christopher D, Lawrence Theodore S, Ramnath Nithya, Wen Fei, Chinnaiyan Arul M, Cieslik Marcin, Alva Ajjai, Zou Weiping