IL-4 Drives Exhaustion of CD8 CART Cells

Overview

Journal Nat Commun

Specialty Biology

Date 2024 Sep 12

PMID 39266501

Authors

Carli M Stewart

Elizabeth L Siegler

R Leo Sakemura

Michelle J Cox

Truc Huynh

Brooke Kimball

Long Mai

Ismail Can

Claudia Manriquez Roman

Kun Yun

Olivia Sirpilla

James H Girsch

Ekene Ogbodo

Wazim Mohammed Ismail

Alexandre Gaspar-Maia

Justin Budka

Jenny Kim

Nathalie Scholler

Mike Mattie

Simone Filosto

Saad S Kenderian

Affiliations

Soon will be listed here.

Abstract

Durable response to chimeric antigen receptor T (CART) cell therapy remains limited in part due to CART cell exhaustion. Here, we investigate the regulation of CART cell exhaustion with three independent approaches including: a genome-wide CRISPR knockout screen using an in vitro model for exhaustion, RNA and ATAC sequencing on baseline and exhausted CART cells, and RNA and ATAC sequencing on pre-infusion CART cell products from responders and non-responders in the ZUMA-1 clinical trial. Each of these approaches identify interleukin (IL)-4 as a regulator of CART cell dysfunction. Further, IL-4-treated CD8 CART cells develop signs of exhaustion independently of the presence of CD4 CART cells. Conversely, IL-4 pathway editing or the combination of CART cells with an IL-4 monoclonal antibody improves antitumor efficacy and reduces signs of CART cell exhaustion in mantle cell lymphoma xenograft mouse models. Therefore, we identify both a role for IL-4 in inducing CART exhaustion and translatable approaches to improve CART cell therapy.

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