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Stat5 antagonizes Tox and CD8 T cell exhaustion to foster a durable effector-like state during chronic antigen exposure

ABSTRACT: Constitutive Stat5a activity antagonized Tox and rewired CD8 T cells away from exhaustion to acquire a durable effector/NK-like state with superior anti-tumor potential Stat5 fostered TEXint, temporally re-engaging the Stat5 pathway, partially reprogrammed the epigenetic landscape of exhaustion and restored effector-like differentiation and function cell formation and partial re-acquisition of effector-biology during this TEXprog-to-TEXint transition,

ORGANISM(S): Mus musculus

PROVIDER: GSE238239 | GEO | 2023/08/31

REPOSITORIES: GEO

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

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

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

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Stat5 antagonizes Tox and CD8 T cell exhaustion to foster a durable effector-like state during chronic antigen exposure

Project description:Stat5 antagonizes Tox and CD8 T cell exhaustion to foster a durable effector-like state during chronic antigen exposure

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

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Tox reinforces the phenotype and longevity of exhausted T-cells in chronic viral infection [day 8 acute vs chronic]

Project description:Chronic CD8 T-cell stimulation in persisting infections or tumors can induce a stable gene expression program, known as T-cell dysfunction or exhaustion, that limits the cell’s effector functions and anti-viral and anti-tumor immunity. Thus far, the underlaying molecular mechanisms that induce and stabilize this phenotype are vaguely understood. We report here that establishing this program requires the thymocyte selection-associated high mobility group-box protein (Tox). Genetic disruption of Tox augments effector function, decreases the expression of PD-1, and significantly enhances immunopathology. These changes are linked to a failure in fixing the dysfunctional phenotype in the critical Tcf1+ progenitor population and to impaired epigenetic programing. Surprisingly, the gains in effector function co-incide with declining numbers of Tcf1+ cells and result ultimately in reduced total numbers of pathogen-specific T-cells. Thus, we establish Tox as a critical factor for the development of T-cell dysfunction and establish a clear link between CD8 T-cell intrinsic suppression of effector function and protection against immune-pathology. The terms acute and chronic samples refer to P14 T-cells that were initially activated in acute LCMV (Armstrong) or chronic LCMV (clone-13) infections. 4 weeks later, the P14 T cells were collected, transferred into naive mice, and both then re-expanded in acute LCMV (Armstrong) infection. 8 days later P14 T-cells were collected and analysed.

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