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Enhanced anti-tumour immunity by the Runx3R122C variant through inducing effector TEXprog development. [ChIP-Seq]

ABSTRACT: The efficacy of immune checkpoint blockade (ICB) relies on CD8⁺ stem/progenitor-exhausted T cells (TEXprog), which give rise to tumour-clearing effector T cells. However, poor responses to ICB and CAR-T therapies are often due to the accumulation of terminally exhausted T cells (TEXterm). Here, we show that the Runx3R122C mis-sense variant suppresses TEXterm differentiation via impairing Runx3-Nfil3 interactions, reducing expression of TEXterm genes Tim-3 and Prdm1. Furthermore, Runx3R122C variant promotes differentiation of novel subtype of TEXprog that possesses both stemness and effector signatures. Anti-tumour effects by such hybrid effector TEXprog are further amplified by ICB. Incorporation of Runx3R122C variant into CD19-CAR-T cells boosts their function and ICB responsiveness. Together with enhanced Natural Killer-mediated anti-tumour responses by Runx3R122C variant, our findings offer novel strategies to anti-cancer immunotherapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE308282 | GEO | 2025/10/20

REPOSITORIES: GEO

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Enhanced anti-tumour immunity by the Runx3R122C variant through inducing effector TEXprog development.

Project description:The efficacy of immune checkpoint blockade (ICB) relies on CD8⁺ stem/progenitor-exhausted T cells (TEXprog), which give rise to tumour-clearing effector T cells. However, poor responses to ICB and CAR-T therapies are often due to the accumulation of terminally exhausted T cells (TEXterm). Here, we show that the Runx3R122C mis-sense variant suppresses TEXterm differentiation via impairing Runx3-Nfil3 interactions, reducing expression of TEXterm genes Tim-3 and Prdm1. Furthermore, Runx3R122C variant promotes differentiation of novel subtype of TEXprog that possesses both stemness and effector signatures. Anti-tumour effects by such hybrid effector TEXprog are further amplified by ICB. Incorporation of Runx3R122C variant into CD19-CAR-T cells boosts their function and ICB responsiveness. Together with enhanced Natural Killer-mediated anti-tumour responses by Runx3R122C variant, our findings offer novel strategies to anti-cancer immunotherapy.

2025-09-30 | GSE308306 | GEO

STAT3 regulates CD8+ T cell differentiation and functions in cancer [RNA-seq]

Project description:In cancer, persistent antigens drive CD8+ T cell differentiation into exhausted progenitor (Texprog) and terminally exhausted (Texterm) cells. However, how the extrinsic and intrinsic regulatory mechanisms cooperate during this process still remain not well understood. Here, we found STAT3 signaling plays essential roles in promoting intra-tumor Texterm cell development, by enhancing their effector functions and survival, which results in better tumor control. In tumor microenvironments, STAT3 is predominantly activated by IL-10 and IL-21, but not IL-6. Besides, STAT3 also plays critical roles in the development and function of terminally differentiated effector CD8+ T cells in acute infection. Mechanistically, STAT3 transcriptionally promotes the expression of effector function-related genes, while suppresses those expressed by progenitor Tex subset. Moreover, STAT3 functions in collaboration with BATF and IRF4 to mediate chromatin activation at effector gene loci. Thus, we have elucidated the roles of STAT3 signaling in terminally differentiated CD8+ T cell development, especially in cancer, which benefits developing more effective immunotherapies against tumor.

2022-12-25 | GSE217375 | GEO

STAT3 regulates CD8+ T cell differentiation and functions in cancer [ChIP-seq]

2022-12-25 | GSE217374 | GEO

STAT3 regulates CD8+ T cell differentiation and functions in cancer [ATAC-seq]

2022-12-25 | GSE217372 | GEO

Enhanced anti-tumour immunity by the Runx3R122C variant through inducing effector TEXprog development.

Project description:Enhanced anti-tumour immunity by the Runx3R122C variant through inducing effector TEXprog development.

| PRJNA1330162 | ENA

Enhanced anti-tumour immunity by the Runx3R122C variant through inducing effector TEXprog development. [ChIP-Seq]

Project description:Enhanced anti-tumour immunity by the Runx3R122C variant through inducing effector TEXprog development. [ChIP-Seq]

| PRJNA1330059 | ENA

A network of intra and extra-tumoural cytotoxic T cells with precursor and residency features constrained by TGF-b

Project description:Anti-tumour immunity is limited by loss of T cell function and sustained expression of inhibitory receptors or immune checkpoints, including PD-1, a state known as T cell exhaustion. Exhausted T cells are maintained by precursors of exhausted T (TPEX) cells, that self-renew and generate effector cells, particularly in response to therapeutic immune checkpoint blockade (ICB). Similarly, tissue-resident memory T (TRM)-like cells have been implicated in tumour control and ICB response. However, the factors governing TPEX and TRM-like cell differentiation and function within the tumour environment, their relationship, and their response to ICB, remain insufficiently understood. Using single cell RNA sequencing and innovative mouse models that enable the identification and targeting of both TPEX and TRM-like cells within and outside the tumour microenvironment, we systemically dissect the developmental and functional relationship between tumour-responsive TPEX cells in the tumour microenvironment and in lymph nodes. We show that within the tumour microenvironment, TPEX cells and their progeny could acquire a tissue residency program that limits their contribution to tumour control and response to checkpoint inhibition. In contrast, stem-like TPEX cells, dependent on the transcription factor MYB and located within the tumour-draining lymph nodes (tdLN), were essential for fueling CD8+ T cell tumour infiltration and response to ICB. We identify TGF-β as the common factor enforcing residency of TPEX cells in the tumour and limiting the abundance of stem-like TPEX cells in tdLN. Finally, we provide evidence for the presence of a similar network of intra- and extratumoural CD8+ T cells in human cancer, exhibiting precursor and residency characteristics that is constrained by TGF-β.

2025-05-27 | GSE253487 | GEO

Bcl6 regulates CD8+ T cell fate decision in cancer [ChIP-Seq]

Project description:Overcoming CD8+ T cell "exhaustion" is critical in cancer immunotherapy. Intra-tumor CD8+ T cells contain stem-like (Texprog) and terminally differentiated (Texterm) subpopulations that mediate the persistence and potency of anti-tumor responses, respectively. How extrinsic signals via transcription factors control these two subsets are unclear. Previously, Bcl6 was shown to be selectively expressed by Texprog cells and promote their generation in chronic infection. Here, we found that in cancer, Bcl6 deficiency impacted, not the generation, but rather the persistence of Texprog cells, thus abrogating long-term tumor control. Bcl6 expression in CD8+ T cells is reciprocally regulated by TGF-?-SMAD2 and IL-2-STAT5 signaling pathways. Blimp1, regulated by IL-2 signaling, potently inhibited Bcl6 expression and its transcriptional activities; Prdm1 deficiency greatly improved the efficacy of anti-PD-1 therapy. Thus, we identified the TGF-?-Bcl6 and IL-2-Blimp1 antagonistic pathways in regulation of anti-tumor CD8+ T cells, which benefits cancer immunotherapy.

2023-08-15 | GSE182034 | GEO

Bcl6 regulates CD8+ T cell fate decision in cancer [RNA-Seq]

2023-08-15 | GSE182035 | GEO

BATF and IRF4 cooperate to counter exhaustion in tumour-infiltrating CAR T cells (RNA-seq)

Project description:Cooperative interactions among transcription factors are essential for gene transcription. We previously showed that NFAT and AP-1 (Fos-Jun) transcription factors cooperate to promote the effector functions of T cells, but that under conditions where it is unable to cooperate with AP-1, NFAT imposes a negative feedback programme of T cell hyporesponsiveness (“exhaustion”). Here we show that BATF and IRF4 cooperate to counter T cell exhaustion. Overexpression of Batf in CD8+ 42 T cells expressing a chimeric antigen receptor (CAR) promoted the survival and expansion of tumour-infiltrating CAR T cells, increased their production of effector cytokines, decreased their expression of inhibitory receptors and the exhaustion-associated transcription factor TOX, and led to the generation of long-lived memory T cells that controlled tumour recurrence. These responses were dependent on the BATF-IRF interaction, since cells expressing a Batf mutant unable to interact with Irf4 did not survive in tumours and did not effectively delay tumour growth. We suggest that BATF overexpression is a therapeutically viable option for improving the anti-tumour responses of CAR TILs, by skewing their phenotypes and transcriptional profiles away from exhaustion and towards increased effector function.

2021-07-13 | GSE154745 | GEO

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