Yu and Green et al. showed that in patients with several types of carcinomas, liver metastasis was associated with poor response to immunotherapy, reduced T cells in the periphery and primary tumors, and limited intratumoral T cell diversity. In anti-PD-L1-responsive mouse s.c. tumor models, liver metastasis voided tumor-specific anti-PD-L1 efficacy. Activated antigen-specific CD44+LFA-1+Fas+CD8+ T cells accumulated in livers, but not s.c. tumors nor their draining lymph nodes. Hepatic FasL+ monocyte-derived macrophages induced Fas-mediated tumor-specific T cell death. Hepatic radiotherapy altered the hepatic chemokine content and rescued the immunotherapy response.
Contributed by Paula Hochman
ABSTRACT: 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.
Author Info: (1) Department of Surgery, University of Michigan, Ann Arbor, MI, USA. (2) Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center,
Author Info: (1) Department of Surgery, University of Michigan, Ann Arbor, MI, USA. (2) Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA. (3) Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA. migr@med.umich.edu. (4) Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA. migr@med.umich.edu. (5) Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, MI, USA. migr@med.umich.edu. (6) Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, MI, USA. (7) Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA. (8) Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA. (9) University of Michigan Medical School, University of Michigan, Ann Arbor, MI, USA. (10) Department of Pathology, University of Michigan, Ann Arbor, MI, USA. (11) Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA. (12) Chemical Engineering, University of Michigan, Ann Arbor, MI, USA. (13) Division of Hematology Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA. (14) Machine Learning Department, Moffitt Cancer Center, Tampa, FL, USA. (15) University of Michigan School of Public Health, Ann Arbor, MI, USA. (16) Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI, USA. (17) Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, MI, USA. (18) Department of Surgery, University of Michigan, Ann Arbor, MI, USA. wzou@med.umich.edu. (19) Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA. wzou@med.umich.edu. (20) Department of Pathology, University of Michigan, Ann Arbor, MI, USA. wzou@med.umich.edu. (21) Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, MI, USA. wzou@med.umich.edu. (22) Graduate Program in Cancer Biology, University of Michigan Medical School, University of Michigan, Ann Arbor, MI, USA. wzou@med.umich.edu.
