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BACH2 regulates T cell lineage states to enhance CAR T cell function [ATAC-seq]

ABSTRACT: Nearly all chimeric antigen receptors (CARs) signal in the absence of antigen, referred to as “tonic signaling”. Tonic signaling of CARs containing the CD28 costimulatory domain has been shown to driveT cell exhaustion; in contrast, we found that tonic signaling of 41BB-containing CARs enhances T cell function. Using a panel of CARs targeting CD22, we identified that tonic 41BB signaling activatesBACH2, a transcriptional regulator that directs stem and memory programs. Overexpression of BACH2 prevented tonic CD28-driven exhaustion but locked CAR T cells in quiescent states. To overcome this, we linked BACH2 to a degradation domain and found that tuning BACH2 expression enhanced long-term efficacy of exhaustion-prone CAR T cells targeting liquid and solid tumors. Through interrogation of CAR products, we also found an association between BACH2 activity and clinical outcomes in patients with leukemia. These data identify a central role for BACH2 in regulating CAR T cell efficacy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE312384 | GEO | 2025/12/08

REPOSITORIES: GEO

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BACH2 regulates T cell lineage states to enhance CAR T cell function [Cut & Run]

Project description:Nearly all chimeric antigen receptors (CARs) signal in the absence of antigen, referred to as “tonic signaling”. Tonic signaling of CARs containing the CD28 costimulatory domain has been shown to driveT cell exhaustion; in contrast, we found that tonic signaling of 41BB-containing CARs enhances T cell function. Using a panel of CARs targeting CD22, we identified that tonic 41BB signaling activatesBACH2, a transcriptional regulator that directs stem and memory programs. Overexpression of BACH2 prevented tonic CD28-driven exhaustion but locked CAR T cells in quiescent states. To overcome this, we linked BACH2 to a degradation domain and found that tuning BACH2 expression enhanced long-term efficacy of exhaustion-prone CAR T cells targeting liquid and solid tumors. Through interrogation of CAR products, we also found an association between BACH2 activity and clinical outcomes in patients with leukemia. These data identify a central role for BACH2 in regulating CAR T cell efficacy.

2025-12-08 | GSE312367 | GEO

Dynamic control of transcriptional regulator BACH2 overcomes T cell dysfunction driven by tonic CAR signaling

Project description:Chimeric antigen receptors (CARs) integrate multiple lymphocyte-derived functional domains to enable selective antigen binding and robust T cell activation in a single synthetic protein. Through various biochemical mechanisms, nearly all CARs activate intracellular signaling in the absence of antigen, referred to as “tonic signaling”. Previous work has shown that tonic signaling of CARs containing the CD28 costimulatory domain drives T cell exhaustion; in contrast, we have shown that tonic signaling of 41BB-containing CARs enhances T cell function. Using a model of tonically signaling CARs targeting the B cell antigen CD22, we undertook studies to determine the molecular determinants of the divergent impact of tonic CAR signaling on T cell fitness. We identified that tonic 41BB signaling induces activation of BACH2, a transcriptional regulator that directs stem and memory programs to maintain T cell homeostasis. Transgenic expression of BACH2 prevented the development of exhaustion and promoted memory-like programs in tonically signaling CD28-containing CAR T cells. This enhanced acute cytotoxic function but impaired durable anti-tumor function. We linked transgenic BACH2 to a degradation domain, enabling precise control of BACH2 expression and found that low-level expression of BACH2 enabled robust and persistent tumor control in multiple cancer models.

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Optimized delivery of dual co-stimulation and anti-tumor activity using parallel chimeric antigen receptors (pCARs)

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Costimulatory domains direct distinct fates of CAR-driven T cell dysfunction [ATAC-seq]

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A Tonic Signaling Code Governs CAR-T Cell Efficacy in Diffuse Midline Glioma

Project description:Diffuse midline glioma (DIPG/DMG) is a uniformly fatal pediatric brain tumor. While CAR T-cell therapy holds promise, clinical responses remain inconsistent, largely due to limited CAR-T persistence and premature exhaustion. Reliable biomarkers to predict therapeutic efficacy are lacking, and proposed T-cell exhaustion or stemness markers offer limited predictive value. Here, we systematically evaluate CAR-T cells against the clinically relevant tumor antigen B7-H3 and identify tonic signaling, antigen-independent CAR activation, as a key determinant of therapeutic performance. B7-H3 CAR-T cells with minimal tonic signaling show superior tumor killing, persistence, and resistance to exhaustion in patient-derived DIPG models. Integrative single-cell and multi-omic profiling identifies a tonic signaling–associated gene signature that consistently outperforms conventional exhaustion or stemness markers in predicting CAR-T efficacy across multiple independent clinical trial datasets, including DIPG/DMG and other tumor types. Thus, our findings establish a mechanistic and predictive framework to guide CAR design and improve clinical outcomes.

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Global phosphoproteomic analysis of signaling by distinct chimeric antigen receptors reveals kinetic and quantitative differences that influence cell function

Project description:Chimeric antigen receptors (CARs) are synthetic proteins that redirect T cell specificity by linking an extracellular ligand binding domain to intracellular T cell signaling domains. CAR-expressing T (CAR-T) cells have demonstrated significant efficacy for the treatment of refractory B cell malignancies and are being evaluated as immunotherapeutic reagents for many other cancers. CAR designs are based on the fundamental principles of TCR recognition and most CARs employ the T cell-activating CD3z endodomain alongside a costimulatory domain from CD28 or 4-1BB. However, emerging data suggest that CD28/CD3z and 4-1BB/CD3z signaling modules promote divergent metabolic pathways, gene expression programs, and cell fates. To determine how CAR phosphoprotein signaling drives these disparate cell fates, we analyzed CAR ligation-induced signaling networks in primary human T cells using shotgun mass spectrometry. We isolated CD8+CD62L+ T cells from healthy donors and introduced a CD28/CD3z or 4-1BB/CD3z CAR by lentiviral transduction. Transduced T cells were purified by FACS and expanded once in vitro. When the cells returned to a resting state, CD28/CD3z or 4-1BB/CD3z CAR-T cells were stimulated for 10 or 45 minutes with magnetic microbeads coated with a monoclonal antibody specific for a 9 amino acid tag in the CAR extracellular sequence. CAR-T cells were also left unstimulated for 10 or 45 minutes to serve as controls. Altogether, 8 unique conditions were tested in an experiment and three independent experiments were performed.

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BACH2 dosage establishes the hierarchy of stemness and fine-tunes antitumor immunity in CAR T cells

Project description:Self-renewing stem-like T cells promote the efficacy of cancer immunotherapy and are a heterogeneous population with sub-lineages demonstrating different degrees of stemness. At the apex of this hierarchy is long-term (LT) stem-like T cells with the highest capacity of persistence, repopulation and response to immune checkpoint inhibitors (ICI). However, the pathway that establishes the hierarchy of stemness in chimeric antigen receptor (CAR) T cells and its role in antitumor efficacy of CAR T cells are unclear. Here, we demonstrate that LT stem-like differentiation and antitumor immunity of CAR T cells are dose-dependently regulated by BACH2. Pre-infusion LT stem-like CAR T cells showed epigenetic activation of BACH2 and superior antitumor response in mice and humans. After clearing tumor in vivo, LT stem-like T cells emerged as a CAR subset that transcriptionally and epigenetically upregulated BACH2 and downregulated TOX. Loss-of-function experiments revealed an essential role of BACH2 in the antitumor response of CAR T cells and the transcriptional program of LT stem-like CAR T cells. In exhaustion-prone GD2 CAR T cells with high tonic signaling, we showed that quantitative control of BACH2 protein level by a small molecule drug fine-tuned the degree of stemness and exhaustion in CAR T cells. Chemically inducing temporal BACH2 activation during manufacture of GD2 CAR T cells imprinted greater antitumor immunity against solid tumor after infusion. Together, we show that BACH2 dosage establishes the hierarchy of stem-like CAR T cells and can be temporally and tunably controlled in CAR T cells to optimize differentiation and antitumor immunity.

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