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Epigenetic regulators of clonal hematopoiesis control CD8 T cell stemness during immunotherapy [ATAC-seq]

ABSTRACT: Epigenetic reinforcement of T cell exhaustion is a major barrier limiting durability of T cell responses during immunotherapy, however the central epigenetic regulators restricting therapy-enabling T cell stemness in settings of prolonged antigen exposure remain to be fully resolved. Here we investigated DNMT3A, TET2, and ASXL1, the three most commonly mutated epigenetic regulators promoting clonal hematopoiesis (CH), to determine if they control the cardinal features of T cell stemness. Using a canonical murine model of exhaustion, we show that CD8 T cells lacking Dnmt3a, Tet2, or Asxl1 are able to preserve an immune checkpoint blockade (ICB) responsive progenitor-exhausted (Tpex) population for over a year during chronic antigen exposure without undergoing malignant transformation. Specific investigation into the lesser-studied regulator, Asxl1, revealed that this unprecedented maintenance of Tpex was achieved through preservation of the cell’s self-renewal capacity with less terminal differentiation. Mechanistic investigation into the role of Asxl1 during CD8 T cell differentiation revealed epigenetic modification of the PR-DUB pathway involving H2AK119-ubiquitination. Extending this Tpex-preserving mechanism to immunotherapy, we report synergy between Asxl1 deficient T cells and anti-PDL1, resulting in heightened tumor control in murine tumor models and a survival advantage to the mutated T cells in treated patients. These data collectively define a core set of epigenetic regulators that control longevity of the stem-like T cell population responsible for clinical success during cancer immunotherapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE274863 | GEO | 2024/10/10

REPOSITORIES: GEO

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Project description:Tumors and chronic infections result in sustained antigen exposure, which promotes impaired functional responsiveness in T cells referred to as exhaustion. Checkpoint immunotherapy can induce the reinvigoration of cellular immunity by activating a recently identified precursor of exhausted T (TPEX) cell population. This activation requires cellular interactions between TPEX cells and professional antigen-presenting cells, likely conventional dendritic cells (cDC). Currently, it is unknown where cDC - TPEX cell interactions take place and which cDC subsets are involved. To address these questions, we first mapped the differentiation trajectory of TPEX cell subsets via transitory cellular states towards terminally exhausted T (TEX) cells, identified transcriptionally distinct subpopulations and defined their localization in the spleen during chronic viral infection. We found that cDC were required for TPEX cell proliferation, differentiation and viral control during PD-L1 treatment. In particular cDC1, a specialized subset of dendritic cells, colocalized with TPEX cells and regulated their maintenance by promoting the functionality of stromal cells that support TPEX cell survival. Additionally, during PD-L1 treatment, the splenic cDC1 network was significantly reorganized at the marginal zone, a site of TPEX cell differentiation. As a consequence, viral control during checkpoint immunotherapy and cellular integrity of the marginal zone depended on the presence of cDC1. Since cDC2 were sufficient to drive initial TPEX cell proliferation and TEX cell generation but not viral control, our data suggest a new concept in which cDC1 decelerate the speed of differentiation of TPEX cells via transitory cellular states and thereby generate a therapeutic window for effective immunotherapy. Together, our findings reveal how the dynamic spatial organization of the DC network supports cellular niches that guide the maintenance and differentiation of TPEX cells and opens new avenues to optimize checkpoint immunotherapy.