Chow et al. showed that pleural and peritoneal cavity-resident Tim-4+ (a phosphatidylserine (PS) receptor) macrophages suppress the efficacy of immunotherapies in these anatomic spaces. Metastatic involvement of serous body cavities is associated with poor clinical outcomes after ICB therapy, and Tim-4 expressed on cavity-resident macrophages is inversely correlated with CD39+CD8+ T cells. Tim-4 abrogation enhanced anti-PD-1 therapy efficacy in mice. PShigh CD8+ T cells showed enhanced expression of proliferation- and cytotoxicity-associated genes and Tim-4+ macrophages functionally sequestered and impaired proliferation of PShigh CD8+ T cells.
Contributed by Shishir Pant
ABSTRACT: Immune checkpoint blockade (ICB) has been a remarkable clinical advance for cancer; however, the majority of patients do not respond to ICB therapy. We show that metastatic disease in the pleural and peritoneal cavities is associated with poor clinical outcomes after ICB therapy. Cavity-resident macrophages express high levels of Tim-4, a receptor for phosphatidylserine (PS), and this is associated with reduced numbers of CD8+ T cells with tumor-reactive features in pleural effusions and peritoneal ascites from patients with cancer. We mechanistically demonstrate that viable and cytotoxic anti-tumor CD8+ T cells upregulate PS and this renders them susceptible to sequestration away from tumor targets and proliferation suppression by Tim-4+ macrophages. Tim-4 blockade abrogates this sequestration and proliferation suppression and enhances anti-tumor efficacy in models of anti-PD-1 therapy and adoptive T cell therapy in mice. Thus, Tim-4+ cavity-resident macrophages limit the efficacy of immunotherapies in these microenvironments.
Author Info: (1) Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Memorial Sloan Kettering Cancer Cent
Author Info: (1) Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA. (2) Weill Cornell Medical College, New York, NY, USA. (3) Department of Radiation Oncology, University of Michigan Rogel Cancer Center and Veterans Affairs Ann Arbor Healthcare System, MI, USA. (4) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA; Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (5) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (6) Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (7) Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (8) Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (9) Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (10) Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (11) Department of Medical Education, University of Michigan School of Medicine, Ann Arbor, MI, USA. (12) Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, MI, USA. (13) Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, NY, USA. (14) Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (15) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (16) Departments of Surgery and Pathology, Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA. (17) Weill Cornell Medical College, New York, NY, USA; Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (18) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA; Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (19) Perlmutter Cancer Center, New York University Langone Health, New York, NY, USA. (20) Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA; Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (21) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA; Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: rudinc@mskcc.org. (22) Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA; Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: merghout@mskcc.org.
