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Y chromosome gene KDM5D coordinates epigenetic and metabolic control of sex differences in CD8⁺ T cell immunity [CUT&Run]

ABSTRACT: Sex differences in anti-tumor immunity remain incompletely understood yet have important implications for tumor biology and immunotherapy. Here, we combine murine colorectal cancer (CRC) models, primary CD8+ T-cell perturbation studies, and single-cell transcriptomic analyses of human CRC to define a male-biased regulatory axis that limits CD8+ T-cell effector function. Male CD8+ T cells displayed reduced cytokine production, proliferation, cytotoxicity, TCR abundance, and TCR signaling relative to female CD8+ T-cells. Mechanistically, depletion of histone demethylase KDM5D, encoded by the Y chromosome, enhanced TCR expression and clustering, increased proximal TCR signaling, reduced cholesterol biosynthetic programs, and lowered expression of exhaustion-associated genes. In human CRC single-cell datasets, male tumor-infiltrating CD8+ T-cells showed enrichment for exhaustion and cholesterol-associated programs, supporting the translational relevance of this axis. Consistent with the known role of cholesterol in TCR clustering and activation, lovastatin reduced exhaustion-associated marker expression in male CD8+ T-cells and delayed CRC tumor growth in vivo – findings which align with the male-specific CRC risk reduction role of statins. Together, these findings identify KDM5D as a sex-chromosome-linked regulator of male CD8+ T-cell dysfunction and validate cholesterol metabolism as an actionable target for sex-specific immunotherapeutic modulation in cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE331334 | GEO | 2026/07/23

REPOSITORIES: GEO

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Similar Datasets

Y chromosome gene KDM5D coordinates epigenetic and metabolic control of sex differences in CD8⁺ T cell immunity [RNA-seq]

Project description:Sex differences in anti-tumor immunity remain incompletely understood yet have important implications for tumor biology and immunotherapy. Here, we combine murine colorectal cancer (CRC) models, primary CD8+ T-cell perturbation studies, and single-cell transcriptomic analyses of human CRC to define a male-biased regulatory axis that limits CD8+ T-cell effector function. Male CD8+ T cells displayed reduced cytokine production, proliferation, cytotoxicity, TCR abundance, and TCR signaling relative to female CD8+ T-cells. Mechanistically, depletion of histone demethylase KDM5D, encoded by the Y chromosome, enhanced TCR expression and clustering, increased proximal TCR signaling, reduced cholesterol biosynthetic programs, and lowered expression of exhaustion-associated genes. In human CRC single-cell datasets, male tumor-infiltrating CD8+ T-cells showed enrichment for exhaustion and cholesterol-associated programs, supporting the translational relevance of this axis. Consistent with the known role of cholesterol in TCR clustering and activation, lovastatin reduced exhaustion-associated marker expression in male CD8+ T-cells and delayed CRC tumor growth in vivo – findings which align with the male-specific CRC risk reduction role of statins. Together, these findings identify KDM5D as a sex-chromosome-linked regulator of male CD8+ T-cell dysfunction and validate cholesterol metabolism as an actionable target for sex-specific immunotherapeutic modulation in cancer.

2026-07-23 | GSE330655 | GEO

Histone demethylase KDM5D upregulation drives sex differences in colon cancer [HiChIP]

Project description:Sex exerts a profound impact on cancer incidence, spectrum and outcomes, yet the molecular genetic bases of such sex differences are ill-defined and presumptively ascribed to X-chromosome genes and sex hormones. Such sex differences are particularly prominent in colorectal cancer (CRC) where men experience higher metastases and mortality. A murine CRC model, engineered with an inducible transgene encoding oncogenic mutant KRASG12D and conditional null alleles of Apc and Trp53 tumor suppressors (designated iKAP), revealed higher metastases and worse outcomes specifically in males with oncogenic mutant KRAS (KRAS*) CRC. Integrated cross-species molecular and transcriptomic analyses identified Y-chromosome gene histone demethylase KDM5D as a transcriptionally up-regulated gene driven by KRAS*-mediated activation of the STAT4 transcription factor. KDM5D-dependent chromatin mark and transcriptome changes showed repression of regulators of the epithelial cell tight junction and MHC class I complex components. Deletion of Kdm5d in iKAP cancer cells increased tight junction integrity, decreased cell invasiveness, and enhanced cancer cell killing by CD8+ T cells. Conversely, iAP mice engineered with a Kdm5d transgene to provide constitutive Kdm5d expression specifically in iAP cancer cells exhibited an increased propensity for more invasive tumors in vivo. Thus, KRAS*-STAT4-mediated upregulation of Y chromosome KDM5D contributes significantly to the sex differences in KRAS* CRC via its disruption of cancer cell adhesion properties and tumor immunity, providing an actionable therapeutic strategy for metastasis risk reduction for men afflicted with KRAS* CRC.

2023-05-13 | GSE232458 | GEO

Histone demethylase KDM5D upregulation drives sex differences in colon cancer [ChIP-Seq]

2023-05-13 | GSE232457 | GEO

Histone demethylase KDM5D upregulation drives sex differences in colon cancer [RNA-Seq]

2023-05-13 | GSE232456 | GEO

Regulation of Sex-biased Gene Expression by the X-Y Chromosomal Gene Pair Kdm5c-Kdm5d in Pluripotent Cells

Project description:Mammalian sex differences are determined by the X and Y chromosomes. Ancestral homologous genes on the sex chromosomes, termed X-Y gene pairs, have been predicted to drive sex differences. However, among the five X-Y gene pairs conserved across eutherians, which pairs drive sex-biased gene expression have remained undefined. Here, we investigate the roles of the X-Y gene pair Kdm5c-Kdm5d in regulating sex-biased gene expression independently of sex hormones using pluripotent mouse embryonic stem cells (ESCs) as a model. Wild-type (WT) XX female and WT XY male ESCs significantly differ in the expression of approximately 4% of all expressed genes, classified as female- or male-biased. Loss of Kdm5c in female ESCs results in the downregulation of female-biased genes. In contrast, loss of either Kdm5c or Kdm5d in male ESCs results in the upregulation of female-biased genes and downregulation of male-biased genes, effectively neutralizing sex-biased gene expression. In male ESCs, most sex-biased genes change in expression in a similar direction upon loss of Kdm5c or Kdm5d. However, Kdm5c loss dysregulates a greater number of sex-biased genes relative to Kdm5d loss in male ESCs. Remarkably, in female ESCs ectopic Kdm5d expression is sufficient to drive a sex-biased gene expression pattern similar to that of WT male ESCs. Taken together, these results establish Kdm5c-Kdm5d as a critical X-Y gene pair in driving sex-biased gene expression in pluripotent cells.

2024-12-13 | GSE277494 | GEO

Direct regulation of T cell exhaustion by NFAT [ChIP-Seq]

Project description:During persistent antigen stimulation, CD8+ cytolytic T cells (CTL) show a gradual decrease in effector function, or “exhaustion”, which impairs the immune response to tumors and infections. Here we show that NFAT, a transcription factor with an established role in T cell activation, in parallel controls a second transcriptional program conferring the characteristic features of CD8+ T cell exhaustion, including upregulation of genes encoding inhibitory cell surface receptors and diminished TCR signaling. Expression of an engineered NFAT1, which induces this negative regulatory program in the absence of the effector program, interferes with the ability of CD8+ T cells to protect against Listeria infection or attenuate tumor growth in vivo. NFAT elicits this second program of gene expression in large part by binding to a subset of the sites occupied by NFAT during a typical effector response, suggesting that a balance between the two pathways determines the outcome of TCR signaling. Determination of NFAT1 binding sites in CD8 T cells in vitro

2015-02-13 | E-GEOD-64407 | biostudies-arrayexpress

Direct regulation of T cell exhaustion by NFAT [RNA-Seq]

2015-02-13 | E-GEOD-64408 | biostudies-arrayexpress

Enhanced antigen cross-presentation in human colorectal cancer-associated fibroblasts through upregulation of the lysosomal protease Cathepsin S

Project description:Cross-presentation of exogenous antigens in HLA-class I molecules by professional antigen presenting cells (APCs) is crucial for CD8+ T cell function. Recent murine studies show that several non-professional APCs, including cancer-associated fibroblasts (CAFs) also possess this capacity. It is currently unknown whether human CAFs are able to cross-present exogenous antigen, which molecular pathways are involved in this process and how this ultimately affects tumor-specific CD8+ T cell function. Here we show that human colorectal cancer (CRC)-derived CAFs display an enhanced capacity to cross-present neoantigen-derived synthetic long peptides (SLPs) when compared to normal colonic fibroblasts. Importantly, cross-presentation of antigens required the lysosomal protease Cathepsin S. Cathepsin S expression by CAFs was detected in situ in human CRC tissue, was upregulated in ex vivo cultured CRC-derived CAFs and showed increased expression in normal fibroblasts after exposure to CRC-conditioned medium. Cognate interaction between CD8+ T cells and cross-presenting CAFs suppressed T cell function, reflected by decreased cytotoxicity, reduced activation (CD25, CD137) and increased exhaustion (TIM3) marker expression. Our data indicate that CAFs may directly suppress tumor-specific T cell function in an antigen-dependent fashion in human CRC.

2022-03-03 | PXD029507 | Pride

An orthotopic organoid-based model to track CD8⁺ T cell exhaustion dynamics in colorectal cancer.

Project description:Colorectal cancer (CRC) treatment represents a major clinical challenge, with immunotherapy providing durable responses in a minority of patients. A deeper understanding of CD8⁺ T cell exhaustion and its contribution to immune checkpoint inhibitor (ICI) responsiveness is essential for the development of more effective therapeutic strategies. Here, we established a syngeneic organoid-based orthotopic CRC mouse model by transplanting quadruple mutant Apc⁻/⁻KrasG12D/+Trp53R172H/⁻Smad4⁻/⁻ (AKPS) intestinal organoids into the rectal submucosa of immunocompetent mice. Single-cell transcriptomic profiling revealed that tumor-infiltrating CD8⁺ T cell phenotypes span a continuum of differentiation states, ranging from precursor exhausted (Tpex) to terminally exhausted (Tex) CD8+ cell subsets. In contrast, subcutaneous implants of AKPS were infiltrated by mixed CD4⁺ and CD8⁺ cell subsets, with CD8⁺ T cells exhibiting a markedly lower exhaustion profile, highlighting the limitations of heterotopic tumor models for studying antitumor immune responses. Functionally, CD8⁺ T cell depletion led to increased tumor burden in orthotopic AKPS implants, underscoring their antitumor activity. Importantly, anti-PD-1 treatment reduced tumor growth, demonstrating the responsiveness of this model to ICIs. Together, our findings establish the AKPS orthotopic CRC model as a powerful platform to dissect the molecular mechanisms of CD8⁺ T cell exhaustion and to preclinically evaluate novel immunotherapeutic interventions in CRC.

2026-05-27 | GSE310071 | GEO

Intermittent Administration of Tacrolimus Enhances Anti-Tumor Immunity in Melanoma-Bearing Mice

Project description:One key reason for T cell exhaustion is continuous antigen exposure. Early exhausted T cells can reverse exhaustion and differentiate into fully functional memory T cells if removed from persisting antigen stimulation. Therefore, this study viewed T cell exhaustion as an over-activation status induced by chronic antigen stimuli. This study hypothesized that blocking TCR signal intermittently to terminate over-activation signal can defer the developmental process of T cell exhaustion. In this study, B16F10 melanoma-bearing mice were treated with tacrolimus (FK506) every five days. The tumor size and tumor-infiltrating lymphocytes (TILs) were analyzed. We found that intermittent administration of tacrolimus significantly inhibited tumor growth, and this effect was mediated by CD8+T cells. Intermittent tacrolimus treatment facilitated the infiltration of CD8+TILs. RNA-seq and quantitative RT-PCR of sorted CD8+TILs showed the expression of Nr4a1 (an exhaustion-related transcription factor) and Ctla4 (a T cell inhibitory receptor) was remarkably downregulated. These results indicated that intermittently blocking TCR signal by tacrolimus can promote anti-tumor immunity and inhibit the tumor growth in melanoma-bearing mice, inhibiting the transcription of several exhaustion-related genes, such as Nr4a1 and Ctla4.

2022-02-03 | GSE190872 | GEO

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