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Inhibiting CXCR4 Attenuates TOX-Programmed Exhausted Phenotype of CD8+ T cells via Regulating JAK2/STAT3 Pathway [ChIP-Seq]

ABSTRACT: T-cell exhaustion (Tex) phenotype has limited the efficacy of single-agent immune checkpoint blockade (ICB) in cancer immunotherapy, underscoring the need to target upstream pathways. Clinical trials have indicated that CXCR4 antagonists enhance anti-cancer activity. However, the specific mechanisms through which CXCR4 contributes to immune cell phenotypes are not fully understood. By targeting CXCR4 using antagonists or transgenic mice (Cxcr4flox/flox LckCre), we effectively attenuated the Tex phenotype and enhanced the functional T-cell phenotype in vivo. Additionally, single-cell RNA/TCR-seq analyses demonstrated that CXCR4 inhibition promotes anti-PD-1 immunotherapy by reducing CD8+ Tex phenotype and enriching the abundance of TCR clonotypes in vivo. Mechanically, we found that CXCR4-blocking T cells mitigate Tex phenotype by regulating the JAK2-STAT3 pathway, reducing the interaction between p-STAT3 and TOX. Single-cell ATAC/RNA-seq validated that CXCR4 deficiency epigenetically orchestrates the transition from functional to exhausted phenotypes in CD8+ T cells. Altogether, we demonstrate a mechanism of targeting CXCR4 to orchestrate CD8+ Tex cells in cancers and provide a rationale for the combined CXCR4 antagonists and ICBs in clinical trials.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE255177 | GEO | 2025/01/28

REPOSITORIES: GEO

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Inhibiting CXCR4 Attenuates TOX-Programmed Exhausted Phenotype of CD8+ T cells via Regulating JAK2/STAT3 Pathway [scRNA_VDJ-seq]

Project description:T-cell exhaustion (Tex) phenotype has limited the efficacy of single-agent immune checkpoint blockade (ICB) in cancer immunotherapy, underscoring the need to target upstream pathways. Clinical trials have indicated that CXCR4 antagonists enhance anti-cancer activity. However, the specific mechanisms through which CXCR4 contributes to immune cell phenotypes are not fully understood. By targeting CXCR4 using antagonists or transgenic mice (Cxcr4flox/flox LckCre), we effectively attenuated the Tex phenotype and enhanced the functional T-cell phenotype in vivo. Additionally, single-cell RNA/TCR-seq analyses demonstrated that CXCR4 inhibition promotes anti-PD-1 immunotherapy by reducing CD8+ Tex phenotype and enriching the abundance of TCR clonotypes in vivo. Mechanically, we found that CXCR4-blocking T cells mitigate Tex phenotype by regulating the JAK2-STAT3 pathway, reducing the interaction between p-STAT3 and TOX. Single-cell ATAC/RNA-seq validated that CXCR4 deficiency epigenetically orchestrates the transition from functional to exhausted phenotypes in CD8+ T cells. Altogether, we demonstrate a mechanism of targeting CXCR4 to orchestrate CD8+ Tex cells in cancers and provide a rationale for the combined CXCR4 antagonists and ICBs in clinical trials.

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Inhibiting CXCR4 Attenuates TOX-Programmed Exhausted Phenotype of CD8+ T cells via Regulating JAK2/STAT3 Pathway [scATAC-seq; scRNA-seq]

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Inhibiting CXCR4 Attenuates TOX-Programmed Exhausted Phenotype of CD8+ T cells via Regulating JAK2/STAT3 Pathway [RNA-Seq]

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Project description:T cells activated by chronic antigen exposure in the setting of viral infections or cancer can adopt an exhausted T cell (TEx) state, characterized by reduced effector function and proliferative capacity, and the upregulation of inhibitory receptors. Here, we generate a single-cell multi-omic atlas of T cell exhaustion in chronic viral infection that redefines the phenotypic diversity and molecular regulation of TEx states. Longitudinal analysis of the T cell response identifies an early effector phenotype that is epigenetically primed for TEx differentiation. However, clonal T cell trajectories defined using paired single-cell RNA and T cell receptor (scRNA/TCR-seq) sequencing reveal divergent differentiation trajectories among clones that recognize shared antigens, resulting in TEx- or effector memory-biased clone behaviors. Multi-organ clonal analysis reveals that T cell clone behaviors are sensitive to the tissue environment, and the liver niche preclude the development of effector memory phenotypes and induce exaggerated exhaustion. Finally, we show that divergent clonal trajectories are driven by differences in TCR affinity, and that high-affinity T cell clones preferentially adopt the divergent fate, while low-affinity clones adopt effector memory fates that are deleted in high antigen niches. These findings reveal heterogeneity in clonal T cell responses to chronic antigen and link TCR signal strength and epigenetic programming to TEx cell fates and persistence, which may be manipulated for cancer immunotherapy.

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Decitabine-induced T cell remodeling facilitates a high antitumor response to PD-1 blockade therapy by promoting the expansion and effector function of CD8+ progenitor exhausted T cells

Project description:CD8+ exhausted T (Tex) cells are heterogeneous with distinct transcriptional and epigenetic landscapes. PD-1 inhibitors reinvigorate progenitor Tex cells, which subsequently differentiate into irresponsive terminal Tex cells and impair the longlasting antitumor response of PD-1 blockade therapy. How to maintain durable proliferative capacity of progenitor Tex cells is important but remains largely unknown. Here, we showed that low-dose DNA demethylating agent decitabine-pretreated CD8+ progenitor Tex cells had enhanced cytolytic activity against tumors after anti-PD-1 treatment in vitro and could not reactivate the terminal Tex cells. Decitabine-plus-anti-PD-1 treatment promoted the activation and expansion of endogenous tumor-infiltrated CD8+ progenitor Tex cells and efficiently suppressed tumor growth in multiple mice tumor models. The single-cell RNA-sequencing, TCR-sequencing and ATAC-sequencing demonstrated that decitabine-plus-anti-PD-1 combination altered the transcriptional and epigenetic status of CD8+ Tex cells and markedly elevated the clonally expansion and effector function of progenitor Tex cells as compared with anti-PD-1 monotherapy, presenting increased expression of genes associated with T cell activation, proliferation, cytolytic activity, memory and mitochondrial metabolism. Strikingly, decitabine-plus-anti-PD-1 combination sustained the expression and activity of AP-1 transcription factor JunD, which was reduced following PD-1 blockade therapy. Suppressing JNK/AP-1 signaling in CD8+ T cells blunted decitabine-plus-anti-PD-1-induced activation of CD8+ T cells. Together, our findings show that the epigenetic therapy remodels CD8+ progenitor Tex subset, improves responsiveness to anti-PD-1 therapy and suppresses CD8+ T cell terminal differentiation.

2022-07-28 | GSE209965 | GEO

Tumor infiltrating exhausted CD8+ T cells dictate divergent survival outcomes in pre- versus post-menopausal estrogen receptor-positive breast cancer

Project description:CD8+ tumor infiltrating lymphocytes (TILs) are associated with improved survival in triple negative breast cancer (TNBC), yet have no association with survival in estrogen receptor-positive (ER+) BC. The basis for these contrasting findings remains elusive. We identify subsets of BC tumors infiltrated by CD8+ T cells with characteristic features of exhausted T cells (TEX). Tumors with abundant CD8+ TEX exhibit a distinct tumor microenvironment marked by amplified interferon-γ signaling related pathways and higher PD-L1 expression. Paradoxically, high levels of CD8+ TEX TILs associate with decreased overall survival ER+ BC patients, but not TNBC patients. Moreover, high tumor expression of a CD8+ TEX signature identifies dramatically reduced survival in pre-menopausal, but not post-menopausal, ER+ BC patients. Finally, we demonstrate the value of a tumor TEX signature score in identifying high-risk pre-menopausal ER+ BC patients amongst those with intermediate Oncotype Dx breast recurrence scores. Our data highlight the complex relationship between CD8+ TILs, interferon-γ signaling, and estrogen receptor status in BC patient survival. This work identifies pre-menopausal ER+ BC patients with high levels of tumor infiltrating CD8+ TEX as a high-risk subset that may benefit from immunotherapy strategies.

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Distinct SWI/SNF chromatin remodelling complexes act differentially to maintain stem-like exhausted CD8 T cells [RNA-seq]

Project description:Exhausted CD8 T cells (TEX) arise during chronic viral infections and cancer and limit disease control. Three major sequential epigenetic remodeling events occur as naïve CD8 T cells (TN) differentiate into TEX: initial activation, early bifurcation between effector (TEFF) and TEX precursors, and later differentiation of effector-like and terminal TEX subsets from progenitor TEX. The epigenetic factors mediating these transitions remain poorly understood. Here, we uncovered distinct roles for two versions of the SWI/SNF chromatin remodeling complex, BAF and PBAF, in TEX differentiation using in vivo CRISPR screening. Disruption of BAF ablated antigen-specific CD8 T cells early in chronic infection, suggesting a requirement for BAF-mediated remodeling in the early epigenetic remodeling events. In contrast, depletion of PBAF subunits enhanced TEX formation and promoted progenitor TEX differentiation into more differentiated TEX subsets by limiting accessibility of TCF-1 binding sites. Loss of PBAF improved tumor control alone and in combination with anti-PD-L1. Simultaneous depletion of BAF- and PBAF-specific subunits revealed that BAF is required for the beneficial impact of loss of PBAF on TEX differentiation. Thus, BAF and PBAF regulate epigenetic transitions in CD8 T cell differentiation, with PBAF acting at a later stage in exhaustion as a guardian to limit full TEX differentiation and preserve TEX progenitor populations with implications for cancer immunotherapy.

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Distinct SWI/SNF chromatin remodelling complexes act differentially to maintain stem-like exhausted CD8 T cells [ATAC-seq]

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TIM-3 + CD8 T cells with a terminally exhausted phenotype retain functional capacity in hematological malignancies

Project description:Chronic antigen stimulation is thought to generate dysfunctional CD8 T cells. Here we identify a CD8 T cell subset in the bone marrow tumor microenvironment that, despite an apparent terminally exhausted phenotype (TPHEX), expressed granzymes, perforin, and IFNγ. Concurrent gene expression and DNA accessibility revealed that genes encoding these functional proteins correlated with BATF expression and motif accessibility. IFNγ+ TPHEX effectively killed myeloma with comparable efficacy to transitory effectors, and disease progression correlated with numerical deficits in IFNγ+ TPHEX. We also observed IFNγ+ TPHEX within CD19-targeted chimeric antigen receptor T cells, which killed CD19+ leukemia cells. Importantly, an IFNγ+ TPHEX gene signature was recapitulated in TEX cells from human cancers, including myeloma and lymphoma. Here we characterize a TEX subset in hematological malignancies that paradoxically retains function and is distinct from dysfunctional TEX found in chronic viral infections. Thus, IFNγ+ TPHEX represent a potential target for immunotherapy of blood cancers.

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