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NR4A transcription factors limit CAR T cell function in solid tumours.
Joyce Chen1,2,3,4, Isaac F López-Moyado5,6,7, Hyungseok Seo5
1Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, CA, USA. jchen@lji.org.
Nature
|March 1, 2019
Summary
Chimeric antigen receptor (CAR) T cells targeting solid tumors become dysfunctional due to NR4A transcription factors. Inhibiting these NR4A factors can restore CAR T cell function for improved cancer immunotherapy.
Area of Science:
- Immunology
- Cancer Biology
- Molecular Biology
Background:
- Chimeric antigen receptor (CAR) T cells are effective against B cell malignancies but less so against solid tumors.
- CAR T cell dysfunction in solid tumors is linked to chronic antigen stimulation and upregulation of inhibitory receptors.
- This hyporesponsive state involves specific transcription factor activation pathways.
Purpose of the Study:
- To investigate the mechanisms of CAR T cell hyporesponsiveness in solid tumors.
- To identify key molecular players involved in CAR T cell dysfunction.
- To explore novel therapeutic targets for enhancing CAR T cell efficacy in cancer immunotherapy.
Main Methods:
- Transfer of human CD19-reactive CAR T cells into CD19+ tumor-bearing mouse models.
- Analysis of gene expression and chromatin accessibility in tumor-infiltrating lymphocytes (TILs).
- Generation and evaluation of NR4A transcription factor triple knockout CAR T cells.
Main Results:
- CD8+ CAR T cells and endogenous TILs in tumors showed similar gene expression profiles linked to NR4A transcription factors.
- NR4A transcription factors were highly expressed in T cells from cancer patients and chronic infections.
- NR4A triple knockout CAR T cells promoted tumor regression, prolonged survival, and exhibited effector T cell phenotypes.
Conclusions:
- NR4A transcription factors play a critical cell-intrinsic role in T cell hyporesponsiveness.
- NR4A inhibition represents a promising strategy to overcome CAR T cell dysfunction in cancer.
- Targeting NR4A factors could enhance the efficacy of CAR T cell therapy for solid tumors.
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