Protection of Regulatory T Cells from Fragility and Inactivation in the Tumor Microenvironment

Overview

Journal Cancer Immunol Res

Specialties Allergy & Immunology
Oncology

Date 2022 Oct 18

PMID 36255418

Authors

Hongru Zhang

Vivek S Tomar

Jinyang Li

Raghavendra Basavaraja

Fangxue Yan

Jun Gui

Noreen McBrearty

Tara Lee Costich

Daniel P Beiting

M Andres Blanco

Jose R Conejo-Garcia

Gurpanna Saggu

Allison Berger

Yulia Nefedova

Dmitry I Gabrilovich

Serge Y Fuchs

Affiliations

Soon will be listed here.

Abstract

Fragility of regulatory T (Treg) cells manifested by the loss of neuropilin-1 (NRP1) and expression of IFNγ undermines the immune suppressive functions of Treg cells and contributes to the success of immune therapies against cancers. Intratumoral Treg cells somehow avoid fragility; however, the mechanisms by which Treg cells are protected from fragility in the tumor microenvironment are not well understood. Here, we demonstrate that the IFNAR1 chain of the type I IFN (IFN1) receptor was downregulated on intratumoral Treg cells. Downregulation of IFNAR1 mediated by p38α kinase protected Treg cells from fragility and maintained NRP1 levels, which were decreased in response to IFN1. Genetic or pharmacologic inactivation of p38α and stabilization of IFNAR1 in Treg cells induced fragility and inhibited their immune suppressive and protumorigenic activities. The inhibitor of sumoylation TAK981 (Subasumstat) upregulated IFNAR1, eliciting Treg fragility and inhibiting tumor growth in an IFNAR1-dependent manner. These findings describe a mechanism by which intratumoral Treg cells retain immunosuppressive activities and suggest therapeutic approaches for inducing Treg fragility and increasing the efficacy of immunotherapies.

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