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Transcriptional regulation of T cell exhaustion in immune checkpoint blockade resistance at single-cell resolution [ex vivo-scATAC]

ABSTRACT: Tumor-specific CD8+ T lymphocytes are crucial for anti-cancer immunity but can lose cytotoxic function in the immunosuppressive tumor microenvironment. Immune checkpoint blockades (ICB), like anti-PD-1 therapy, enhance and prolong anti-tumor T cell responses. Despite its widespread clinical use, resistance to ICB develops in some patients, characterized by the proliferation of exhausted T cell (Tex). Here, we establish two single-cell murine hepatocellular carcinoma (HCC) models to explore regulatory network in Tex with ICB resistance. We uncover distinct T cell compositions, including both early and terminal Tex subsets, following prolonged ICB treatment, and reveal the differentiation trajectory of Tex subsets. Finally, we not only identify transcription factor Runx2 and its downstream targets as contributors to T cell exhaustion in both models, but discover ICB response correlates to Runx2 level in human tumor-infiltrating lymphocytes. These findings elucidate Runx2 regulates T cell exhaustion in response to prolonged ICB treatment, influencing ICB effICBency, and suggest potential targets for combination therapy alongside ICB in HCC.

ORGANISM(S): Mus musculus

PROVIDER: GSE268160 | GEO | 2025/12/17

REPOSITORIES: GEO

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Transcriptional regulation of T cell exhaustion in immune checkpoint blockade resistance at single-cell resolution [ex vivo-scRNA]

Project description:Tumor-specific CD8+ T lymphocytes are crucial for anti-cancer immunity but can lose cytotoxic function in the immunosuppressive tumor microenvironment. Immune checkpoint blockades (ICB), like anti-PD-1 therapy, enhance and prolong anti-tumor T cell responses. Despite its widespread clinical use, resistance to ICB develops in some patients, characterized by the proliferation of exhausted T cell (Tex). Here, we establish two single-cell murine hepatocellular carcinoma (HCC) models to explore regulatory network in Tex with ICB resistance. We uncover distinct T cell compositions, including both early and terminal Tex subsets, following prolonged ICB treatment, and reveal the differentiation trajectory of Tex subsets. Finally, we not only identify transcription factor Runx2 and its downstream targets as contributors to T cell exhaustion in both models, but discover ICB response correlates to Runx2 level in human tumor-infiltrating lymphocytes. These findings elucidate Runx2 regulates T cell exhaustion in response to prolonged ICB treatment, influencing ICB effICBency, and suggest potential targets for combination therapy alongside ICB in HCC.

2025-12-17 | GSE268161 | GEO

Transcriptional regulation of T cell exhaustion in immune checkpoint blockade resistance at single-cell resolution [in vivo]

Project description:Tumor-specific CD8+ T lymphocytes are crucial for anti-cancer immunity but can lose cytotoxic function in the immunosuppressive tumor microenvironment. Immune checkpoint blockade (ICB), like anti-PD-1 therapy, enhance and prolong anti-tumor T cell responses. Despite its widespread clinical use, resistance to ICB develops in some patients, characterized by the proliferation of exhausted T cell (Tex). Here, we establish two single-cell murine hepatocellular carcinoma (HCC) models to explore regulatory network in Tex with ICB resistance. We uncover distinct T cell compositions, including both early and terminal Tex subsets, following prolonged ICB treatment, and reveal the differentiation trajectory of Tex subsets. Finally, we not only identify transcription factor Runx2 and its downstream targets as contributors to T cell exhaustion in both models, but discover ICB response correlates to Runx2 level in human tumor-infiltrating lymphocytes. These findings elucidate Runx2 regulates T cell exhaustion in response to prolonged ICB treatment, influencing ICB effICBency, and suggest potential targets for combination therapy alongside ICB in HCC.

2025-12-17 | GSE268163 | GEO

Chronic Type I interferons signaling promotes lipid peroxidation-driven terminal CD8+T cell exhaustion and curtails anti-PD-1 treatment efficacy

Project description:Identifying signals that govern the differentiation of tumor-infiltrating CD8 + T cells (CD8 + TILs) towards exhaustion can improve current therapeutic approaches for cancer. Here, we show that type I interferons (IFN-Is) act as environmental cues enhancing terminal CD8 + T cell exhaustion in tumors. We found enrichment of IFNIs-stimulated genes (ISGs) within exhausted CD8 + T cells (Tex cells) in patients across various cancer types, with heightened ISG levels correlating with poor response to immune checkpoint blockade (ICB) therapy. In preclinical models, CD8 + TILs devoid of IFN-Is signaling developed less exhaustion features, provided better tumor control and showed greater response to ICB-mediated rejuvenation. Mechanistically, chronic IFN-Is stimulation perturbed lipid metabolism and redox balance in Tex cells, leading to aberrant lipid accumulation and elevated oxidative stress. Collectively, these defects promoted lipid peroxidation, which potentiated metabolic and functional exhaustion of Tex cells. Thus, cell intrinsic IFN-Is signaling regulates the extent of CD8+ TIL exhaustion, and has important implications for immunotherapy.

2022-11-16 | GSE212699 | GEO

Chronic Type I interferons signaling promotes lipid peroxidation-driven terminal CD8+T cell exhaustion and curtails anti-PD-1 treatment efficacy [ATAC-Seq]

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Chronic Type I interferons signaling promotes lipid peroxidation-driven terminal CD8+T cell exhaustion and curtails anti-PD-1 treatment efficacy [RNA-Seq]

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EZH2 loss during metabolic stress drives restoration of MHC Class I machinery in melanoma

Project description:Unleashing the immune anti-tumor response through immune checkpoint blockade (ICB) has been successful in treating many solid-tumor malignancies, including metastatic melanoma. When successful, the ICB response can be potent; however, half of patients fail to respond. ICB responsiveness is impacted by the harsh solid tumor microenvironment (TME), which is characterized by metabolic stress. The TME impacts tumor antigenicity, with ICB-responsive melanomas exhibiting increased major histocompatibility complex class I (MHC-I) expression. Further investigation of tumor immunogenicity in the context of the TME may improve cellular therapies. Here, we define and characterize an epigenetic mechanism regulating melanoma antigen presentation driven by prolonged metabolic stress. Murine and human melanoma cell lines were cultured under prolonged metabolic stress, forcing cells to adapt to the absence of glucose. Melanoma cells adapted to the absence of glucose have IFN-gamma-independent increases in MHC-I and an increased sensitivity to T cell-mediated killing. Proteomic analysis revealed dysregulation of histone epigenetic modifiers under prolonged metabolic stress, specifically loss of histone methyltransferase EZH2 (Enhancer of Zeste Homolog 2). EZH2 directly silences gene transcription via catalyzing H3K27me3. Following metabolic adaptation, ChIP-sequencing and ChIP-PCR revealed H3K27me3 loss at genes specific to MHC-I antigen presentation. Prolonged metabolic stress in melanoma cells blunt EZH2 levels and H3K27me3 levels at promoters of genes regulating MHC-I presentation, resulting in elevated MHC-I antigenicity and increased CD8+ T cell killing. This demonstrates potential for EZH2 abundance and mutational status as a prognostic indicators of ICB-responsiveness in metastatic melanoma and supports EZH2 inhibition as adjuvant for immunotherapies

2024-08-13 | MSV000095589 | MassIVE

Activated-ATF6α is an ER stress-inducing oncoprotein metabolically restricting immunosurveillance [bulk RNA-seq of TG-AAV-GFP/CRE, DEN/HFD]

Project description:Hepatocellular carcinoma (HCC) is the fastest growing cause of cancer-related mortality with limited therapies. While endoplasmic reticulum (ER)-stress and the unfolded protein response (UPR) are implicated in HCC, the involvement of the UPR-transducer activating transcription factor 6 alpha (ATF6α) remains unclear. In contrast to the well-characterized role of ATF6α-activation as an adaptive response to ER-stress, we here demonstrate its hitherto unknown function as an ER stress-inducing oncoprotein and metabolic master-regulator restricting cancer-immunosurveillance. In human HCC, ATF6α-activation significantly correlated with reduced patient-survival, tumor-progression, local immunosuppression, and higher recurrence rates of liver-cancer upon hepatectomy. Hepatocyte-specific ATF6α-activation in mice induced progressive hepatitis with ER-stress, immunosuppression, and hepatocyte-proliferation. Concomitantly, activated-ATF6α increased glycolysis and repressed gluconeogenic enzyme fructose-1,6-bisphosphatase 1 (FBP1). Restoring FBP1 expression prevented ATF6α-activation-related pathologies. Prolonged ATF6α-activation in hepatocytes triggered hepatocarcinogenesis, intratumoral T-cell infiltration, and nutrient-deprived immune-exhaustion. Immune-checkpoint blockade (ICB) efficiently restored immunosurveillance and dramatically reduced HCC. In line, HCC patients with a significantly higher ATF6α-activation signature presented complete response to ICB monotherapy. Targeting Atf6 via germline, hepatocyte-specific ablation, or therapeutic delivery of antisense-oligonucleotides dampened HCC in preclinical liver-cancer models. Thus, prolonged ATF6α-activation drives ER-stress, leading to aberrant glucose metabolism-dependent immunosuppression in liver cancer. Our findings propose persistently activated ATF6α as an oncoprotein, stratification-marker for liver-cancer ICB, and targetable therapeutic strategy against HCC.

2025-11-16 | GSE244342 | GEO

Activated-ATF6α is an ER stress-inducing oncoprotein metabolically restricting immunosurveillance [bulk RNAseq of TG-AAV-GFP/CRE/FBP1]

2025-11-16 | GSE244341 | GEO

Activated-ATF6α is an ER stress-inducing oncoprotein metabolically restricting immunosurveillance [bulk RNA-seq of Atf6 KO DEN/HFD]

2025-11-16 | GSE244343 | GEO

B16 vs Res499 Whole Exome Sequencing

Project description:Interferon-gamma (IFNG) augments immune function yet promotes T cell exhaustion through PDL1. How these opposing effects are integrated to impact immune checkpoint blockade (ICB) is unclear. We show that while inhibiting tumor IFNG signaling decreases interferon-stimulated genes (ISGs) in cancer cells, it increases ISGs in immune cells by enhancing IFNG produced by exhausted T cells (TEX). In tumors with favorable antigenicity, these TEX mediate rejection. In tumors with neoantigen or MHC-I loss, TEX instead utilize IFNG to drive maturation of innate immune cells, including a PD1+TRAIL+ ILC1 population. By disabling an inhibitory circuit impacting PD1 and TRAIL, blocking tumor IFNG signaling promotes innate immune killing. Thus, interferon signaling in cancer cells and immune cells oppose each other to establish a regulatory relationship that limits both adaptive and innate immune killing. In melanoma and lung cancer patients, perturbation of this relationship is associated with ICB response independent of tumor mutational burden.

2019-08-13 | GSE132035 | GEO

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