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Expression data from CD8 T cells from LCMV-Clone13 infected mice after two weeks of control or anti-PD-L1 treatment

ABSTRACT: Blocking PD-1 can reinvigorate exhausted CD8 T cells (TEX) and improve control of chronic infections and cancer. One potential advantage of this immunotherapy is durable protection if immune memory can be established. It is unclear, however, whether blocking PD-1 can reprogram TEX into effector (TEFF) or durable memory T cells (TMEM). Here, we found reinvigoration of TEX by PD-L1 blockade caused re-acquisition of some features of TEFF, but minimal memory development. We used microarray analysis to profile exhausted cells from anti-PD-L1 mice after two weeks of treatment to study if PD-L1 blockade caused re-acquistion of some feature of effector or memory cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE86796 | GEO | 2016/10/31

SECONDARY ACCESSION(S): PRJNA342514

REPOSITORIES: GEO

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Combined PD-L1/TGFb blockade allows expansion and differentiation of stem cell-like CD8 T cells in immune excluded tumors

Project description:TGFb signaling is a major pathway associated with poor clinical outcome in patients with advanced metastatic cancers and non-response to immune checkpoint blockade, particularly in the immune-excluded tumor phenotype. While previous pre-clinical studies demonstrated that converting tumors from an excluded to an inflamed phenotype and curative anti-tumor immunity require attenuation of both PD-L1 and TGFb signaling, the underlying cellular mechanisms remain unclear. Recent studies suggest that stem cell-like CD8 T cells (TSCL) can differentiate into non-exhausted CD8 T effector cells that drive durable anti-tumor immunity. Here, we show that TGFb and PD-L1 restrain TSCL expansion as well as replacement of progenitor exhausted and dysfunctional CD8 T cells with non-exhausted IFNghi CD8 T effector cells in the tumor microenvironment (TME). Blockade of TGFb and PD-L1 generated IFNghi CD8 T effector cells with enhanced motility, enabling both their accumulation in the TME and increased interaction with other cell types. Ensuing IFNg signaling markedly transformed myeloid, stromal, and tumor niches to yield a broadly immune-supportive ecosystem. Blocking IFNg completely abolished the effect of anti-PD-L1/ TGFb combination therapy. Our data suggest that TGFb works in concert with PD-L1 to prevent TSCL expansion and replacement of exhausted CD8 T cells with fresh CD8 T effector cells, thereby maintaining the CD8 T cell compartment in a dysfunctional state.

2023-06-16 | MSV000092193 | MassIVE

Enhanced STAT5a activation opposes Tox and rewires exhausted CD8 T cells towards a hybrid durable effector-like state during chronic stimulation [ATAC-postChallenge]

Project description:Here, we discovered a reciprocal antagonism between Stat5a and Tox in TEX cells. Stat5a antagonized the Tox-mediated exhaustion program to achieve a durable and protective hybrid effector/NK-like differentiation state in settings that typically drive exhaustion. Stat5 also drove TEX progenitors to differentiate into the effector-like TEXint subset, a key developmental step for PD-1 blockade responsiveness. Therapeutic enhancement of Stat5 activity in TEX cells using an orthogonal IL-2/IL2Rb pair system fostered TEXint cell accumulation and synergized with PD-L1 blockade. Finally, targeted delivery of Stat5-signals in TEX progenitors achieved partial epigenetic rewiring of these cells towards the effector/memory lineage and revived polyfunctionality. Together, these data highlight therapeutic opportunities of targeting Stat5 to antagonize the Tox-dependent epigenetic programming of TEX and provoke a hybrid program that exploits effector biology and durability for optimal therapeutic potential

2023-05-31 | GSE214112 | GEO

Enhanced STAT5a activation opposes Tox and rewires exhausted CD8 T cells towards a hybrid durable effector-like state during chronic stimulation [ATAC-postInfection]

2023-05-31 | GSE214111 | GEO

Enhanced STAT5a activation opposes Tox and rewires exhausted CD8 T cells towards a hybrid durable effector-like state during chronic stimulation [ATAC-Seq]

2023-08-31 | GSE240431 | GEO

The chromatin state in WT and HPK1KO tumor specific T cells

Project description:We then investigated how HPK1 induces new changes by comparing the open chromatin regions (OCRs) with WT control and founded that the ATAC-seq tracks were aligned with the previously reported OCRs of exhausted . HPK1 knockout induced loss of peaks in loci enriched in exhausted T (Tex) cells (e.g., PD-1, TIM-3, LAG-3, and TOX locus), indicating that HPK1 knockout could overcome some negative effects caused by TME, ameliorate T cell exhaustion and thus extend their effector function (Figure S2F). Moreover, we also found that more accessible regions in HPK1-knockout CD8+TILs showed significant enrichment for pathways associated with cell cycle, antigen processing and presentation, T cell receptor signaling, Glyoxylate and dicarboxylate metabolism, AMPK pathway, and C-type lectin receptor signaling pathway (Figure S2G). It has been demonstrated that many peak changes were unique to either the early dysfunctional or functional state and included TCR signaling and cytokine production pathway genes. Pauken and the colleagues identified two metagenes in anti-PD-L1–treated exhausted T cell (TEX) compared to control TEX; one corresponding to leukocyte activation and one to cell cycle. The anti-PD-L1–treated TEX metagenes displayed some overlap with effector T cells (TEFF), largely driven by cell cycle pathways, but minimal overlap with Memory T cell (TMEM). Thus, we concluded that HPK1-/- TILs are prone to be effort T cells defined according to the chromatin states.

2020-05-16 | GSE150635 | GEO

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 CD8+ Tex cells dictate divergent survival outcomes in pre- vs post-menopausal ER+ breast cancer

Project description: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.

2022-02-23 | GSE190169 | GEO

RNA sequencing of human CD8+ T cell subsets [TEX]

Project description:RNA sequencing of human CD8+ T cell subsets to compare hypofunctional exhausted cells (TEX) to fully activated effector cells (TEFF).

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Dual Relief of T-Lymphocyte Proliferation and Effector Function Underlies Response to PD-1 Blockade in Epithelial Malignancies

Project description:Although understanding of T-cell exhaustion is widely based on mouse models, its analysis in cancer patients could provide clues indicating tumor sensitivity to immune checkpoint blockade (ICB). Data suggests a role for costimulatory pathways, particularly CD28, in exhausted T-cell responsiveness to PD-1/PD-L1 blockade. Here, we used single-cell transcriptomic, phenotypic, and functional approaches to dissect the relation between CD8+ T-cell exhaustion, CD28 costimulation, and tumor specificity in head and neck, cervical, and ovarian cancers. We found that memory tumor-specific CD8+ T cells, but not bystander cells, sequentially express immune checkpoints once they infiltrate tumors leading, in situ, to a functionally exhausted population. Exhausted T cells were nonetheless endowed with effector and tumor residency potential but exhibited loss of the costimulatory receptor CD28 in comparison to their circulating memory counterparts. Accordingly, PD-1 inhibition improved proliferation of circulating tumor-specific CD8 T cells and reversed functional exhaustion of specific T cells at tumor sites. In agreement with their tumor specificity, high infiltration of tumors by exhausted cells was predictive of response to therapy and survival in ICB-treated head and neck cancer patients. Our results showed that PD-1 blockade–mediated proliferation/reinvigoration of circulating memory T cells and local reversion of exhaustion occur concurrently to control tumors.

2020-05-01 | GSE148162 | GEO

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.

2023-05-31 | GSE211410 | GEO

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