Immunity I L nine signaling redirects C A R T cell fate toward C D eight positive memory and C D four positive cycling states, enhancing antitumor efficacy

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Immunity I L nine signaling redirects C A R T cell fate toward C D eight positive memory and C D four positive cycling states, enhancing antitumor efficacy

In brief

Castelli et al. show that incorporating interleukin-nine I L nine signaling reprograms chimeric antigen receptor C A R T cells to expand, persist, and resist dysfunction in solid tumors. This strategy improves antitumor activity at lower doses, suggesting a promising way to enhance the effectiveness of C A R T cell therapies against solid cancers.

Highlights

. Engineering C A R T cells with I L nine signaling boosts efficacy against solid tumors

. I L nine-signaling C D four positive C A R T cells have increased T H one and proliferative phenotypes

. Single-cell profiling reveals that I L nine redirects C D eight positive T cell fate away from dysfunction

. I L nine-induced S T A T one/S T A T four activation contributes to improved C A R T cell function

I L nine signaling redirects C A R T cell fate toward C D eight positive memory and C D four positive cycling states, enhancing antitumor efficacy

INTRODUCTION

RESULTS

IL-nine signaling enhances CAR T cell expansion, persistence, and tumor infiltration in vivo

Immunity Article

Article

IL-9 treatment enhances CAR T cell effector phenotype and reduces dysfunction under antigen stress

CD4+ Proliferating

RNA velocity and TF analyses provide mechanistic insights into how IL-9 signaling redirects CAR T cell fate

DISCUSSION

Limitations of the study

RESOURCE AVAILABILITY

Materials availability

Data and code availability

AUTHOR CONTRIBUTIONS

DECLARATION OF INTERESTS

STAR*METHODS

SUPPLEMENTAL INFORMATION

STAR*METHODS

Mice

Immunity Article

METHOD DETAILS

Murine CAR T cell production

Human CAR T cell production

Phosphoflow signaling assay

Article

CAR T cell in vitro dysfunction model

Cytokine production assays

In vitro cytotoxicity assays

Xenograft animal models

Syngeneic animal model

Caliper measurements of subcutaneous tumors

Processing of tumors and spleens

Peripheral blood CAR T cell analysis

Cytokine analysis from mouse serum

Immunohistochemistry

Flow cytometry and sorting

Single-cell RNA sequencing

Single-cell RNA sequencing data quality control

Single-cell RNA sequencing data analysis

CRISPR/Cas9-Mediated STAT4 deletion

Validation of STAT4 deletion

QUANTIFICATION AND STATISTICAL ANALYSIS

Overview

The research demonstrates the potential of I L nine signaling in improving C A R T cell therapies for solid tumors by reprogramming these cells to be more effective against immunosuppressive tumor environments. The findings highlight that engineered C A R T cells with I L nine can achieve superior tumor control and persistence compared to conventional approaches.

Key Points

1Incorporating I L nine signaling into C A R T cells enhances their efficacy against solid tumors
2I L nine signaling promotes a more effective T cell memory and effector state
3The approach decreases the dose required for antitumor efficacy
4Enhanced persistence and tumor infiltration of C A R T cells is observed with I L nine signaling
5The unique expression profile of I L nine receptor minimizes toxicity risks in T cells.

Details

Authors: Castelli et al.
Category: Biology and Natural Sciences

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