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3D genome of CD8+ T cells reveals IRF8-mediated exhaustion in cancer [Hi-C]

ABSTRACT: CD8+ T cell responses are essential for anti-tumor immunity, but chronic antigen exposure in cancer can lead to T cell exhaustion, marked by high PD-1 expression. Recent studies have identified progenitor-like CD8+ T cells (Tprog cells) within tumor-infiltrating lymphocytes (TILs) that sustain antitumor responses. These cells can differentiate into terminally exhausted cells (Tterm cells), losing their proliferative and effector functions. Immunotherapy aims to enhance CD8+ TILs functionality, promoting their transition from Tprog to Tterm cells. However, the mechanisms behind this exhaustion remain unclear. Single-cell RNA sequencing and ATAC-seq have revealed distinct profiles and chromatin accessibility between progenitor and terminally exhausted states. Histone modifications predict a loss of enhancer-promoter contacts during this transition. Chromatin structure plays a crucial role in T cell differentiation. We constructed a high-resolution 3D genome map of CD8+ T cell subsets and, through multi-omics integration, identified chromatin structure changes linked to T cell exhaustion, including alterations in topologically associating domains (TADs) and chromatin loops, providing new insights into the genetic basis of CD8+ T cell exhaustion in cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE299305 | GEO | 2025/10/01

REPOSITORIES: GEO

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3D genome of CD8+ T cells reveals IRF8-mediated exhaustion in cancer

Project description:CD8+ T cell responses are essential for anti-tumor immunity, but chronic antigen exposure in cancer can lead to T cell exhaustion, marked by high PD-1 expression. Recent studies have identified progenitor-like CD8+ T cells (Tprog cells) within tumor-infiltrating lymphocytes (TILs) that sustain antitumor responses. These cells can differentiate into terminally exhausted cells (Tterm cells), losing their proliferative and effector functions. Immunotherapy aims to enhance CD8+ TILs functionality, promoting their transition from Tprog to Tterm cells. However, the mechanisms behind this exhaustion remain unclear. Single-cell RNA sequencing and ATAC-seq have revealed distinct profiles and chromatin accessibility between progenitor and terminally exhausted states. Histone modifications predict a loss of enhancer-promoter contacts during this transition. Chromatin structure plays a crucial role in T cell differentiation. We constructed a high-resolution 3D genome map of CD8+ T cell subsets and, through multi-omics integration, identified chromatin structure changes linked to T cell exhaustion, including alterations in topologically associating domains (TADs) and chromatin loops, providing new insights into the genetic basis of CD8+ T cell exhaustion in cancer.

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Project description:Blockade of programmed death-1 (PD-1) reinvigorates exhausted CD8+ T cells, resulting in tumor regression in cancer patients. Recently, reinvigoration of exhausted CD8+ T cells following PD-1 blockade was shown to be CD28-dependent in mouse models. Herein, we examined the role of CD28 in anti-PD-1-induced human T-cell reinvigoration using tumor-infiltrating CD8+ T cells (CD8+ TILs) obtained from non-small cell lung cancer patients. Single cell analysis demonstrated a distinct expression pattern of CD28 between mouse and human CD8+ TILs. Furthermore, we found that human CD28+CD8+, but not CD28–CD8+ TILs, responded to PD-1 blockade irrespective of B7/CD28 blockade, indicating that CD28 co-stimulation in human CD8+ TILs is dispensable for PD-1 blockade-induced reinvigoration, and loss of CD28 expression rather serve as a marker of anti-PD-1-unresponsive CD8+ TILs. Transcriptionally and phenotypically, PD-1 blockade-unresponsive human CD28–PD-1+CD8+ TILs exhibited characteristics of terminally exhausted CD8+ T cells with low TCF1 expression. Notably, CD28–PD-1+CD8+ TILs had preserved machinery to respond to IL-15, and IL-15 treatment enhanced proliferation of CD28–PD-1+CD8+ TILs as well as CD28+PD-1+CD8+ TILs. Taken together, we demonstrate loss of CD28 expression as a marker of PD-1 blockade-unresponsive human CD8+ TILs with TCF1– signature and provide mechanistic insights into combining IL-15 with anti-PD-1.

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dd195318-5103-4c2e-9845-d48e04787b77 - samples

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Memory-like HCV-specific CD8+ T cells retain a chronic scar after cure of chronic HCV infection

| EGAS00001004538 | EGA

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

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.

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