Jul 2026· Journal of Immunology· Vol 215· 0 citations
TL;DR
These findings identify a novel microbial SCFA as a potential metabolic-epigenetic regulator, capable of reactivating effector programs in TEX cells while blocking terminal exhaustion, and provide insights into developing new therapeutic approaches to reprogram TEX cells and enhance the efficacy of T cell immunotherapy.
Abstract
Exhaustion of CD8 T cells during cancer or chronic infections remains a significant barrier to T cell immunotherapies. Recent studies showed that distinct epigenetic changes drive exhaustion by silencing effector and memory-related genes, thereby establishing the dysfunctional state of exhausted T cells (TEX). Thus, targeting epigenetic regulation of exhaustion is crucial for restoring TEX cell function. Short-chain fatty acids (SCFAs) are emerging as key mediators linking cellular metabolism to gene regulation. Notably, certain SCFAs naturally produced by human microbiota have been shown to modulate host immune responses through epigenetic mechanisms.
To investigate their effects on TEX cell epigenetic programming, we utilized innovative in vitro T cell exhaustion models that generate stable terminal dysfunction in both human and mouse CD8 T cells. By inducing a state of exhaustion that recapitulates key molecular and functional features observed in cancer and chronic infections, these models enabled us to assess how SCFA treatment affects T cell function and memory-associated stemness features.
We discovered that a specific microbial SCFA triggered a significant recovery of polyfunctionality and memory programs within both human and mouse dysfunctional T cells. SCFA-treated TEX cells exhibited renewed effector capabilities, such as enhanced cytokine production, degranulation, and tumor-killing activity. The enhanced effector functions persisted even following termination of SCFA treatment, suggesting stable reprogramming of TEX cells.
These findings identify a novel microbial SCFA as a potential metabolic-epigenetic regulator, capable of reactivating effector programs in TEX cells while blocking terminal exhaustion. These results provide insights into developing new therapeutic approaches to reprogram TEX cells and enhance the efficacy of T cell immunotherapy.
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Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)
This emerging view frames exhaustion as a context-dependent extension of the memory program rather than its collapse, and highlights how these insights can inform new approaches to manipulate T cell fate for therapeutic benefit.
Daniel T. Utzschneider, Stephen J. Turner· Trends in immunology· 0 citations
In autoimmunity and chronic infection, both settings of persistent (self or foreign) antigen, immune responses are sustained by stem-like CD8 T cells, which self-renew and give rise to differentiated progeny. However, if and how T stemness is epigenetically encoded, which transcription factor(s) regulate the stem-T cells, and whether the stem-T cell state is disease-specific or shared across diseases, is currently not known.
We used clinically relevant models of autoimmune type 1 diabetes (T1D) and chronic infection and conducted serial T cell transplantation studies in vivo, combined with single cell paired RNA- and ATAC-sequencing on antigen-specific T cells. We developed CRISPR/Cas9-mediated gene-editing approaches in primary T cells as well as CUT&RUN studies, identifying a novel hierarchy of transcription factors regulating stem T cell identity and function.
We discovered that a small subset of stem-T cells (TSC) express lymphoid enhancer-binding factor 1 (LEF1), a member of the TCF/LEF TF family. Paired single cell transcriptomic and epigenomic analyses reveal that the LEF1+ TSC harbor a unique epigenetically encoded molecular state enriched in genes and pathways characteristic of embryonic and adult (somatic) stem cells (e.g. neural stem cells). Strikingly, we found that TSC in chronic infection harbor a LEF1+ TSC pool sharing the core stemness epigenetic and molecular program observed in autoimmune LEF1+ TSC. Loss- and gain-of-function studies in both autoimmune T1D and chronic infection confirmed the critical role of LEF1 in maintaining T cell stemness. CUT&RUN analyses provide clues as to how LEF1 instructs the epigenetically encoded program of stem-T cells.
Here we reveal novel insights into the molecular circuitries of CD8 T cell stemness and differentiation. We discover LEF1 as the master regulator defining T cell stemness and identify novel targets for therapeutic intervention.
NIH R01AI173249, JDRF SRA-2023-1410-S-B, MSKCC Basic Research Innovation Award, The Hearst Foundation
Lymphocyte Differentiation and Peripheral Maintenance (LYM)
Katrina M. Hawley, S. Miakicheva, P. Zumbo et al.· Journal of Immunology· 0 citations
PI3Kδ inhibition programs T cells with stemness and metabolic fitness that favor Tpex differentiation, resist terminal exhaustion, and remodel the TME toward an inflammatory state, supporting a practical strategy to improve ACT efficacy in solid tumors.
Alexandrea Turnquist, Azka Javaid, F. Kolling et al.· Journal of Immunology· 0 citations
A complementary therapeutic strategy is discussed: engineering T cells for greater durability in the TME through knockout of exhaustion-associated transcription factors, and reprogramming tumour cells with DNA methyltransferase (DNMTi) and histone deacetylase (HDACi) inhibitors to restore immunogenicity.
L. Saltis, Liew Jun Mun· Pathology, Research and Prac...· 0 citations
Epigenetic scarring restricts the long-term function of exhausted CD8 T cells (TEX), impairing their ability to control chronic infections and tumors, or to respond effectively to immunotherapy. While our prior work established that de novo DNA methylation reinforces terminal exhaustion, how upstream histone modifications influence these methylation programs remains largely unknown. Defining these molecular mechanisms is essential for reversing exhaustion and enhancing the durability of T cell immunotherapies.
We employed a novel in vitro model of human CD8 T cell dysfunction alongside preclinical murine models of T cell exhaustion. Using integrative epigenomic approaches, we profiled H3K4 methylation states (H3K4me1/3) and DNA methylation signatures across distinct TEX subsets. To investigate functional relevance, we performed CRISPR/Cas9-gene editing, retroviral transduction, and pharmacological inhibition of histone demethylases to assess their impact on TEX functions, stemness, and response to immune checkpoint blockade (ICB).
While distinct histone and DNA methylation landscapes defined TEX subsets in both human and murine models, H3K4me1/3–histone marks that inhibit Dnmt3a-mediated DNA methylation–were enriched at effector/memory-associated genes in cytolytic/progenitor TEX but diminished in terminally exhausted cells. Genetic or therapeutic inhibition of specific H3K4 demethylases (KDM5A/B) improved effector function and cytotoxicity in dysfunctional human CD8 T cells. In vivo, KDM5A/B targeting enhanced TEX fitness and responsiveness to anti-PD-L1 therapy during chronic viral infection and cancer.
Our findings uncover a central histone—DNA methylation circuit, regulated by KDM5A/B and DNMT3A, that drives epigenetic scarring and terminal exhaustion in CD8 T cells. Therapeutic targeting of this circuit offers a novel approach to epigenetically reprogram TEX cells and enhance the efficacy of cancer immunotherapy.
R01AI170926 (NIH, NIAID)
Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)
Hazem E. Ghoneim, Amira Yousif, Abbey A. Saadey et al.· Journal of Immunology· 0 citations
PD-1 inhibition has revolutionized cancer therapy. However, despite the initial success of immune checkpoint inhibitors (ICIs) across several cancer types, this approach remains ineffective for most patients. Studies indicate that T cell exhaustion (Tex) is epigenetically encoded, and PD-1 blockade can only partially restore T cell activity. Chronic, non-resolving inflammation fosters an immunosuppressive tumor microenvironment (TME) that promotes T cell exhaustion and contributes to immunotherapy resistance. Our goal is to promote the resolution of inflammation through the administration of D-series resolvins (RvDs) to restore leukocyte antitumor activity and reverse immunosuppression and immunotherapy resistance within the TME.
We employed in vitro and in vivo models of HPV-positive head and neck cancer (HNC). Activated CD8+ T cells, isolated from human peripheral blood, were co-cultured with either tumor cell lines or primary tumor cells derived from patient biopsies. Cultures were stimulated with RvD5, a pro-resolving lipid mediator that promotes the resolution of inflammation. Syngeneic and NGS mouse models were treated with RvD5, anti-PD-1, and/or anti-CTLA-4 immunotherapies. Samples were analyzed by flow cytometry, cytokine profiling, lipidomics, bulk RNA sequencing, and single-cell RNA sequencing.
We found that RvD5 reduced PD-1 expression on T cells and PD-L1 expression on cancer cells, thereby restoring T cell antitumor functions by delaying their differentiation into Tex. In vivo, RvD5 inhibited tumor growth. Notably, when combined with anti-PD-1 therapy, RvD5 enhanced tumor response rates, suggesting that shifting cancer-associated inflammation toward resolution can improve ICI efficacy.
Thus, RvD5 suppresses tumor growth by dampening inflammation and delaying T cell exhaustion within the TME. By reshaping CD8+ T cell responses, RvDs may represent a promising therapeutic strategy to strengthen antitumor immunity and overcome resistance to immunotherapy.
AIRC (MFAG 2022 — ID. 27060)
Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)
Maria Tredicine, Simona D'Orazio, Nunzia Coletta et al.· Journal of Immunology· 0 citations
