RRC ID 70122
Author Chow A, Schad S, Green MD, Hellmann MD, Allaj V, Ceglia N, Zago G, Shah NS, Sharma SK, Mattar M, Chan J, Rizvi H, Zhong H, Liu C, Bykov Y, Zamarin D, Shi H, Budhu S, Wohlhieter C, Uddin F, Gupta A, Khodos I, Waninger JJ, Qin A, Markowitz GJ, Mittal V, Balachandran V, Durham JN, Le DT, Zou W, Shah SP, McPherson A, Panageas K, Lewis JS, Perry JSA, de Stanchina E, Sen T, Poirier JT, Wolchok JD, Rudin CM, Merghoub T.
Title Tim-4+ cavity-resident macrophages impair anti-tumor CD8+ T cell immunity.
Journal Cancer Cell
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.
Volume 39(7)
Pages 973-988.e9
Published 2021-7-12
DOI 10.1016/j.ccell.2021.05.006
PII S1535-6108(21)00272-5
PMID 34115989
PMC PMC9115604
MeSH Animals Apoptosis CD8-Positive T-Lymphocytes / immunology* Cell Proliferation Colonic Neoplasms / immunology* Colonic Neoplasms / metabolism Colonic Neoplasms / pathology Female Gene Expression Regulation, Neoplastic* Humans Macrophages / immunology* Membrane Proteins / genetics Membrane Proteins / metabolism* Mice Mice, Inbred BALB C Mice, Inbred C57BL Prognosis Retrospective Studies Tumor Cells, Cultured Tumor Microenvironment* Xenograft Model Antitumor Assays
IF 26.602
Mice RBRC04895