Liver metastasis restrains immunotherapy efficacy via macrophage-mediated T cell elimination

Autor: C.A. Schonewolf, Christopher D. Lao, Ajjai Alva, Xueting Lang, Ilona Kryczek, Fengyun Su, Jiali Yu, Alangoya Tezel, Yilun Sun, Kyle C. Cuneo, Arul M. Chinnaiyan, Meredith A. Morgan, Syed Monem Rizvi, Linda Vatan, Issam El Naqa, Rohan K. Achar, Shuang Wei, Charles S. Mayo, Theodore S. Lawrence, Long Jiang, Wojciech Szeliga, Zoey Chopra, Nithya Ramnath, Weiping Zou, Sara Journey, Jiajia Zhou, Marcin Cieslik, Vincent T. Ma, Jae Eun Choi, Jeremy Skvarce, Xuhong Cao, Shasha Li, Fei Wen, Jessica Waninger, Yingjie Bian, Merna Sitto, Michael D. Green, Angel Qin, B.S. Rosen, Sathiya Pandi Narayanan
Rok vydání: 2021
Předmět:
Zdroj: Nature Medicine. 27:152-164
ISSN: 1546-170X
1078-8956
Popis: 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. Liver metastases reduce clinical and preclinical immune-checkpoint inhibitor efficacy through hepatic siphoning of circulating activated CD8+ T cells, but therapeutic benefit can be improved by combining immunotherapy with liver-directed radiotherapy.
Databáze: OpenAIRE
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