Tim-4 Cavity-resident Macrophages Impair Anti-tumor CD8 T cell Immunity

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2021 Jun 11

PMID 34115989

Citations 76

Authors

Andrew Chow

Sara Schad

Michael D Green

Matthew D Hellmann

Viola Allaj

Nicholas Ceglia

Giulia Zago

Nisargbhai S Shah

Sai Kiran Sharma

Marissa Mattar

Joseph Chan

Hira Rizvi

Hong Zhong

Cailian Liu

Yonina Bykov

Dmitriy Zamarin

Hongyu Shi

Sadna Budhu

Corrin Wohlhieter

Fathema Uddin

Aditi Gupta

Inna Khodos

Jessica J Waninger

Angel Qin

Geoffrey J Markowitz

Vivek Mittal

Vinod Balachandran

Jennifer N Durham

Dung T Le

Weiping Zou

Sohrab P Shah

Andrew McPherson

Katherine Panageas

Jason S Lewis

Justin S A Perry

Elisa de Stanchina

Triparna Sen

John T Poirier

Jedd D Wolchok

Charles M Rudin

Taha Merghoub

Affiliations

Soon will be listed here.

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.

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