Interruption of the Intratumor CD8 T cell:Treg Crosstalk Improves the Efficacy of PD-1 Immunotherapy

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2024 Jun 11

PMID 38861924

Authors

Shannon N Geels

Alexander Moshensky

Rachel S Sousa

Claire Murat

Matias A Bustos

Benjamin L Walker

Rima Singh

Stacey N Harbour

Giselle Gutierrez

Michael Hwang

Thorsten R Mempel

Casey T Weaver

Qing Nie

Dave S B Hoon

Anand K Ganesan

Shivashankar Othy

Francesco Marangoni

Affiliations

Soon will be listed here.

Abstract

PD-1 blockade unleashes potent antitumor activity in CD8 T cells but can also promote immunosuppressive T regulatory (Treg) cells, which may worsen the response to immunotherapy. Tumor-Treg inhibition is a promising strategy to improve the efficacy of checkpoint blockade immunotherapy; however, our understanding of the mechanisms supporting tumor-Tregs during PD-1 immunotherapy is incomplete. Here, we show that PD-1 blockade increases tumor-Tregs in mouse models of melanoma and metastatic melanoma patients. Mechanistically, Treg accumulation is not caused by Treg-intrinsic inhibition of PD-1 signaling but depends on an indirect effect of activated CD8 T cells. CD8 T cells produce IL-2 and colocalize with Tregs in mouse and human melanomas. IL-2 upregulates the anti-apoptotic protein ICOS on tumor-Tregs, promoting their accumulation. Inhibition of ICOS signaling before PD-1 immunotherapy improves control over immunogenic melanoma. Thus, interrupting the intratumor CD8 T cell:Treg crosstalk represents a strategy to enhance the therapeutic efficacy of PD-1 immunotherapy.

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