Non-conventional Inhibitory CD4Foxp3PD-1 T Cells As a Biomarker of Immune Checkpoint Blockade Activity

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2018 Jun 13

PMID 29894689

Citations 81

Authors

Roberta Zappasodi

Sadna Budhu

Matthew D Hellmann

Michael A Postow

Yasin Senbabaoglu

Sasikanth Manne

Billel Gasmi

Cailian Liu

Hong Zhong

Yanyun Li

Alexander C Huang

Daniel Hirschhorn-Cymerman

Katherine S Panageas

E John Wherry

Taha Merghoub

Jedd D Wolchok

Affiliations

Soon will be listed here.

Abstract

A significant proportion of cancer patients do not respond to immune checkpoint blockade. To better understand the molecular mechanisms underlying these treatments, we explored the role of CD4Foxp3 T cells expressing PD-1 (4PD1) and observed that 4PD1 accumulate intratumorally as a function of tumor burden. Interestingly, CTLA-4 blockade promotes intratumoral and peripheral 4PD1 increases in a dose-dependent manner, while combination with PD-1 blockade mitigates this effect and improves anti-tumor activity. We found that lack of effective 4PD1 reduction after anti-PD-1 correlates with poor prognosis. Mechanistically, we provide evidence that mouse and human circulating and intra-tumor 4PD1 inhibit T cell functions in a PD-1/PD-L1 dependent fashion and resemble follicular helper T cell (T)-like cells. Accordingly, anti-CTLA-4 activity is improved in T deficient mice.

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