BACH2 dosage establishes the hierarchy of stemness and fine-tunes antitumor immunity in CAR T cells
Top Cited Papers
Open Access
- 16 January 2026
- journal article
- research article
- Published by Springer Nature in Nature Immunology
- Vol. 27 (3) , 425-435
Abstract
Stem-like T cells promote the efficacy of immunotherapy and are heterogeneous in stemness, with long-term (LT) stem-like T cells at the apex of this hierarchy. How the stemness hierarchy is regulated in chimeric antigen receptor (CAR) T cells and how it affects antitumor function are unclear. Here we show that BACH2 dose-dependently regulates LT stem-like differentiation and antitumor immunity of CAR T cells. LT stem-like CAR T cells that appear before infusion and re-emerge after tumor clearance have superior antitumor immunity and the greatest BACH2 expression. BACH2 promotes the antitumor response of CAR T cells and the LT stem-like transcriptional program. Temporal and quantitative induction of BACH2 expression in CAR T cells during manufacturing using chemical switches fine-tunes the degree of stemness and imprints greater control of solid tumors. Together, these data show that BACH2 dosage defines stemness hierarchy in CAR T cells and can be temporally and tunably controlled to optimize differentiation and antitumor efficacy.Keywords
Funding Information
- U.S. Department of Health & Human Services | National Institutes of Health (AI158294)
- U.S. Department of Health & Human Services | National Institutes of Health (AG083398)
- U.S. Department of Health & Human Services | National Institutes of Health (AG056524)
- U.S. Department of Health & Human Services | National Institutes of Health (AI154450)
- Cancer Research Institute (Clinic & Laboratory Integration Program)
- Cancer Research Institute (Lloyd J. Old STAR Program)
- V Foundation for Cancer Research (V Scholar Award)
- American Federation for Aging Research (Grant for Junior Faculty)
- Cancer Prevention and Research Institute of Texas (RR210035)
- Cancer Prevention and Research Institute of Texas (RP250282)
- U.S. Department of War (HT94252310801)
This publication has 64 references indexed in Scilit:
- CXCR5+ follicular cytotoxic T cells control viral infection in B cell folliclesNature Immunology, 2016
- Defining CD8+ T cells that provide the proliferative burst after PD-1 therapyNature, 2016
- Follicular CXCR5-expressing CD8+ T cells curtail chronic viral infectionNature, 2016
- T Cell Factor 1-Expressing Memory-like CD8+ T Cells Sustain the Immune Response to Chronic Viral InfectionsImmunity, 2016
- Generation of clinical-grade CD19-specific CAR-modified CD8+ memory stem cells for the treatment of human B-cell malignanciesBlood, 2016
- CD19 CAR immune pressure induces B-precursor acute lymphoblastic leukaemia lineage switch exposing inherent leukaemic plasticityNature Communications, 2016
- ChIPmentation: fast, robust, low-input ChIP-seq for histones and transcription factorsNature Methods, 2015
- 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptorsNature Medicine, 2015
- BACH2 mediates negative selection and p53-dependent tumor suppression at the pre-B cell receptor checkpointNature Medicine, 2013
- A Rapid, Reversible, and Tunable Method to Regulate Protein Function in Living Cells Using Synthetic Small MoleculesCell, 2006