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Updated: Jan 14, 2026
In Vitro Tumor Cell Rechallenge For Predictive Evaluation of Chimeric Antigen Receptor T Cell Antitumor Function
Published on: February 27, 2019
Enhanced FOS expression improves tumor clearance and resists exhaustion in NR4A3-deficient CAR T cells under chronic
Peidi Yin1,2, Jigui Yang2, Yiyang Jiang1,2
1Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, P.R. China.
Abstract:
The dysfunction of chimeric antigen receptor (CAR) T cells in the tumor microenvironment is a major obstacle to their therapeutic efficacy against solid tumors. Through single-cell RNA sequencing analysis of tumor-infiltrating T cells from patients with glioma, NR4A family genes were identified as closely associated with T cell exhaustion and were coexpressed with dysfunctional genes HAVCR2 and TIGIT. Notably, CAR T cells with NR4A3 knockdown exhibited enhanced cytotoxic activity against tumors, leading to improved tumor clearance and prolonged survival in vivo. However, the promoted antiexhausted phenotype diminished with prolonged tumor burden. This decline in T cell function correlates with the compensatory down-regulation of FOS induced by chronic antigen exposure following NR4A3 knockdown. Overexpressing FOS alongside NR4A3 knockdown robustly boosted the antitumor responses of CAR T cells by skewing their phenotypes and transcriptional profiles away from exhaustion and toward increased effector function. These findings offer a promising strategy for the clinical modification of CAR T cell therapy.
Insights
Chimeric antigen receptor (CAR) T cell exhaustion in solid tumors can be overcome by targeting NR4A3 and FOS genes. Modulating these genes enhances CAR T cell antitumor activity and improves patient survival.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Chimeric antigen receptor (CAR) T cell therapy shows promise for solid tumors but is hindered by T cell dysfunction within the tumor microenvironment.
- Identifying key regulators of T cell exhaustion is crucial for enhancing CAR T cell efficacy.
Purpose of the Study:
- To investigate the role of NR4A family genes in CAR T cell exhaustion in glioma.
- To explore strategies for overcoming T cell dysfunction and improving CAR T cell antitumor responses.
Main Methods:
- Single-cell RNA sequencing of tumor-infiltrating T cells from glioma patients.
- Genetic manipulation of NR4A3 and FOS in CAR T cells.
- In vivo studies assessing tumor clearance and survival.
Main Results:
- NR4A family genes, including NR4A3, were identified as key drivers of T cell exhaustion, coexpressed with HAVCR2 and TIGIT.
- NR4A3 knockdown enhanced CAR T cell cytotoxicity and in vivo antitumor activity.
- Chronic antigen exposure led to FOS downregulation, diminishing the anti-exhaustion effect, which was restored by FOS overexpression alongside NR4A3 knockdown.
Conclusions:
- Targeting NR4A3 and FOS represents a viable strategy to enhance CAR T cell function and overcome exhaustion in solid tumors.
- Combined NR4A3 knockdown and FOS overexpression significantly boosts CAR T cell antitumor responses, offering a promising therapeutic approach.
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