A central histone—DNA methylation circuit, regulated by KDM5A/B and DNMT3A, that drives epigenetic scarring and terminal exhaustion in CD8 T cells is uncovered and Therapeutic targeting of this circuit offers a novel approach to epigenetically reprogram TEX cells and enhance the efficacy of cancer immunotherapy.
Abstract
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)
An epigenetic approach is described that facilitates the reversal of repressive DNA methylation and is used to alter the fate of T cell subsets for immunotherapy and is now used to alter the fate of T cell subsets for immunotherapy.
A. Norman, Ben Youngblood, Caitlin C. Zebley· Journal of Immunology· 0 citations
Coactivator-associated arginine methyltransferase 1 (CARM1/PRMT4) is a signal-responsive epigenetic regulator that couples oncogenic and stress signals to chromatin, transcription, RNA processing, metabolism, and genome maintenance. Its effects arise from both asymmetric arginine methylation of histone and non-histone substrates and methyltransferase-independent scaffolding activities. This review critically synthesizes the structural basis, substrate networks, methylarginine readers, and cancer-contextual functions of CARM1. We propose that its apparently opposing oncogenic and tumor-suppressive activities are determined by lineage-specific substrates, regulatory post-translational modifications, cofactor and chromatin availability, and stage- or microenvironment-dependent stress signals. We further evaluate CARM1-directed therapy using an evidence-graded framework. Catalytic inhibitors such as TP-064 and EZM2302 differ in binding mode and substrate coverage, whereas emerging degraders can remove scaffolding functions but remain constrained by delivery, E3-ligase heterogeneity, pharmacokinetics, and therapeutic-window uncertainties. Biomarker-guided synthetic-lethal and immunotherapy combinations may therefore offer the most tractable route to clinical translation. This framework positions CARM1 as a context-conditioned signal-to-chromatin translator rather than a uniformly druggable oncogene.
Lu-Yao Zhu, Ya-Jie Liang, Qi-Qi Mao et al.· Biochimica et biophysica act...· 0 citations
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.
Asmaa M. Yousif, Amira Yousif, Ava Lowin et al.· Journal of Immunology· 0 citations
Immune checkpoint blockade (ICB) has revolutionized head and neck squamous cell carcinoma (HNSCC) treatment. Yet, a major barrier to response is that tumor cells are epigenetically reprogrammed to resist immunogenic cell death, particularly pyroptosis. To elucidate how tumor cells are pre-conFigured for pyroptosis resistance, we investigated the role of post-translational modifications on epigenetic regulators, focusing on the phosphorylation-dependent control of histone demethylase KDM6A. Through integrated phosphoproteomics and functional genomics in HNSCC models, we identified phosphorylation of KDM6A at Ser829 as a master regulatory switch. Mechanistically, phosphorylation at Ser829 subverts KDM6A function, leading to a global accumulation of repressive H3K27me3 marks. This establishes an epigenetic program that locks key pyroptosis effector genes (
GSDMD
,
NLRP3
) in a transcriptionally refractory, heterochromatic state. To pharmacologically dismantle this barrier, we developed a novel lipid nanoparticle (LNP) system encapsulating mRNA encoding a phosphorylation-defective
KDM6A
S829A
variant. This strategy functionally reverses the oncogenic epigenetic state, restoring endogenous demethylase activity specifically at pyroptosis loci and reigniting the cell death pathway. In vivo, a single administration of
KDM6A
S829A
mRNA inhibited tumor growth by 39% (
p
< 0.01). Strikingly, when combined with anti-PD-1, this strategy achieved a synergistic 79% tumor reduction (
p
< 0.0001), characterized by robust CD8
+
T cell infiltration. Our work identifies KDM6A phosphorylation as a druggable epigenetic-immune checkpoint and establishes mRNA-based modulation of enzyme post-translational status as a transformative paradigm to potentiate ICB in HNSCC.
Yikang Ji, Xinran Zhao, Cheng Hu et al.· Cell Death & Disease· 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
Naïve T cells maintain a delicate balance between quiescence and rapid activation, which involves multiple layers of regulation beyond transcription. Here, we identify the RNA modification N6,2’-O-dimethyladenosine (m6Am) and its methyltransferase PCIF1 as critical enforcers of T cell quiescence. During CD4+ T cell activation, m6Am levels are dynamically downregulated. T-cell-specific PCIF1 knockout (cKO) mice exhibit potent tumor suppression, driven by enhanced Th1 differentiation and subsequent amplification of NK cell cytotoxicity. Mechanistically, PCIF1 represses STAT1 translation via m6Am modification of its mRNA, thereby constraining Th1 commitment. Activation-induced PCIF1 downregulation releases this translational brake, enabling rapid Th1 polarization. Crucially, we identify Suramin as a pharmacological PCIF1 inhibitor that disrupts m6Am modification, boosts Th1 responses, and suppresses tumor growth. Our findings establish the PCIF1-m6Am-STAT1 axis as a translational checkpoint governing T cell differentiation and suggest that targeting PCIF1 represents a potential strategy for tumor immunotherapy. Phosphorylated CTD interaction factor 1(PCIF1) is the sole enzyme catalyzing the post-transcriptional N6-methyladenosine(m6A) modification for mRNA. Here the authors show, by genomic deletion of PCIF1specifically in T cells, that PCIF1 represses STAT1 translation via this important mRNA modification, and thereby preventing T cell activation and enforcing a naïve T cell phenotype.
Jiansong Huang, Jing Zhou, Xiao Liu et al.· Nature Communications· 1 citation
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