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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

ABSTRACT: 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

PROVIDER: PRJNA863246 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR20694218_1.fastq.gz	Fastqsanger.gz
	SRR20694218_2.fastq.gz	Fastqsanger.gz
	SRR20694219_1.fastq.gz	Fastqsanger.gz
	SRR20694219_2.fastq.gz	Fastqsanger.gz
	SRR20694220_1.fastq.gz	Fastqsanger.gz

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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

Decitabine priming increases anti-PD-1 antitumor efficacy by promoting CD8+ progenitor exhausted T cell expansion in tumor models.

Project description:CD8+ exhausted T cells (Tex) are heterogeneous. PD-1 inhibitors reinvigorate progenitor Tex, which subsequently differentiate into irresponsive terminal Tex. The ability to maintain a capacity for durable proliferation of progenitor Tex is important, but the mechanism remains unclear. Here, we showed CD8+ progenitor Tex pretreated with decitabine, a low-dose DNA demethylating agent, had enhanced proliferation and effector function against tumors after anti-PD-1 treatment in vitro. Treatment with decitabine plus anti-PD-1 promoted the activation and expansion of tumor-infiltrated CD8+ progenitor Tex and efficiently suppressed tumor growth in multiple tumor models. Transcriptional and epigenetic profiling of tumor-infiltrated T cells demonstrated that the combination of decitabine plus anti-PD-1 markedly elevated the clonal expansion and cytolytic activity of progenitor Tex compared with anti-PD-1 monotherapy and restrained CD8+ T cell terminal differentiation. Strikingly, decitabine plus anti-PD-1 sustained the expression and activity of the AP-1 transcription factor JunD, which was reduced following PD-1 blockade therapy. Downregulation of JunD repressed T cell proliferation, and activation of JNK/AP-1 signaling in CD8+ T cells enhanced the antitumor capacity of PD-1 inhibitors. Together, epigenetic agents remodel CD8+ progenitor Tex populations and improve responsiveness to anti-PD-1 therapy.

| S-EPMC10065084 | biostudies-literature

TIGIT and PD-L1 co-blockade promotes clonal expansion of multipotent, non-exhausted antitumor T cells by facilitating co-stimulation

Project description:Blockade of the immune checkpoints PD-1 and TIGIT has demonstrated activity in mouse tumor models and human patients with cancer. Although these coinhibitory receptors can restrict signaling in CD8+ T cells by regulating their associated co-stimulatory receptors CD28 and CD226, the functional consequences of combining PD-1 and TIGIT blockade remain poorly characterized. In mouse tumor models, we show that combination blockade elicited CD226-driven clonal expansion of tumor antigen-specific CD8+ T cells. The expanded clones emerged from a population of stem-like cells in draining lymph nodes, entering the blood as a previously unidentified single-phenotype, multiclonal population. Upon reaching the tumor, these transiting cells expanded further and differentiated into effector or exhausted T cells, with combination blockade restricting entry into the exhaustion pathway by favoring co-stimulation. Thus, PD-1 and TIGIT inhibition helps shape the repertoire of tumor-reactive CD8+ T cells in draining lymph nodes and determines their immunological fate in the tumor to enhance therapeutic benefit. Analysis of clinical trial samples suggests a similar mechanism may also occur in patients with cancer.

2024-12-31 | GSE220901 | GEO

Increasing of antitumor effect of decitabine against classical Hodgkin lymphoma (cHL) by targeting decitabine-activated pro-survival pathways

Project description:We found that 5-Aza-dC/decitabine induces various prosurvival pathways (JAK-STAT-, NFkB-, MEK/ERK- and PI3K/AKTpathway) in cHL cell lines. Inhibition of these pathways with specific small molecular weight inhibitors potentiates the antitumor effect of 5-Aza-dC.

2017-08-01 | GSE86068 | GEO

TIGIT and PD-L1 co-blockade promotes clonal expansion of multipotent, non-exhausted antitumor T cells by facilitating co-stimulation

Project description:TIGIT and PD-L1 co-blockade promotes clonal expansion of multipotent, non-exhausted antitumor T cells by facilitating co-stimulation

| PRJNA911822 | ENA

Epigenetic inflexibility of exhausted T cells limits durability of reinvigoration by PD-1 blockade

Project description:Upon PD-1 pathway blockade,the epigenetic landscape of exhausted cells was only minimally remodeled consistent with lineage commitment and re-exhaustion of these cells over time.

2016-10-31 | GSE86797 | GEO

Myeloid Niches Sustain Antitumor T Cells and License PD-1 Blockade via CD28 Costimulation

Project description:The local mechanisms regulating exhaustion of tumor-infiltrating lymphocytes (TILs) and responsiveness to PD-1 blockade remain partly elucidated. In human ovarian cancer we show that tumor-reactive intraepithelial (ie)CD8+ TILs engaged by antigen are polyfunctional and upregulate PD-1, which restrains their effectiveness. PD-1+ TILs exhibit a continuum of TCR-engaged/exhausted states with variable effector fitness related to CD28 costimulation, which they receive in intraepithelial niches involving myeloid antigen-presenting cells (mAPC). Following PD-1 blockade, activation of TILs requires CD28 costimulation mediated in situ by tumor mAPCs, which is locally enhanced by CTLA-4 blockade. CD40 ligand also amplifies TIL responses in situ, especially in tumors in which mAPCs are not activated. Thus, dysfunctional and exhausted TILs, in a state of TCR engagement but without proper CD28 costimulation by mAPCs in situ, are unlikely to fully benefit from PD-1 blockade.

2021-10-12 | GSE178245 | GEO

Gene expression comparison of exhausted CD8 T cells that respond or do not respond to PD-1 blockade

Project description:CD8 T cells that respond to PD-1 blockade (during the early stage of infection) have enriched CD28 costimulation genes During the early stages of chronic infection PD-1 blockade is effective are rescuing exhausted CD8 T cells. However during the later stages of chronic infection PD-1 blockade is not able to induce a significant rescue of exhausted T cells. In order to understand the transcriptional basis of these difference we performed an RNA comparison. There is enrichment in several genes and pathways, and we hypothesize that these could be exploited for optimizing immune checkpoint therapies during the later stages of chronic infection.

2019-05-01 | GSE118201 | GEO

VEGF blockade enhances the antitumor effect of BRAFV600E inhibition

Project description:VEGF blockade enhances the antitumor effect of BRAFV600E inhibition

| PRJNA286655 | ENA

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

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