Journal Article

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

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

2021

Overview

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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/250/1619/554 / 631/250/2504/342 / 631/67/322 / 631/67/580 / 692/699/67/1059/2325 / Animal models / Animals / Antigens / Apoptosis / Biomarkers / Biomedical and Life Sciences / Biomedicine / Cancer / Cancer Research / Carcinoma, Non-Small-Cell Lung - immunology / Carcinoma, Non-Small-Cell Lung - secondary / Carcinoma, Non-Small-Cell Lung - therapy / Care and treatment / CD11b antigen / CD8 antigen / CD95 antigen / Cell Line, Tumor / Cell survival / Clonal deletion / Cohort Studies / Combined Modality Therapy / Fas antigen / FasL protein / Female / Hepatocytes / Humans / Immune checkpoint inhibitors / Immunological tolerance / Immunotherapy / Infectious Diseases / Liver / Liver cancer / Liver Neoplasms - immunology / Liver Neoplasms - secondary / Liver Neoplasms - therapy / Liver Neoplasms, Experimental - immunology / Liver Neoplasms, Experimental - secondary / Liver Neoplasms, Experimental - therapy / Lymphocyte Activation / Lymphocytes / Lymphocytes T / Macrophages / Macrophages - immunology / Male / Melanoma - immunology / Melanoma - secondary / Melanoma - therapy / Metabolic Diseases / Metastases / Metastasis / Methods / Mice / Mice, Inbred C57BL / Mice, Transgenic / Molecular Medicine / Monocytes / Neurosciences / Patient outcomes / Physiological aspects / Radiation therapy / Radiotherapy, Adjuvant / Siphoning / T cells / T-Lymphocytes - classification / T-Lymphocytes - immunology / T-Lymphocytes - pathology / Treatment Failure / Treatment Outcome / Tumor Microenvironment - immunology / Tumor Microenvironment - radiation effects