Epigenetic regulators of clonal hematopoiesis control CD8 T cell stemness during immunotherapy

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Presentation Time: 11:30 AM - 12:45 PM
Poster Board Number: B205
Abstract ID: 4169

Presenting Author:
Tae Gun Kang , Postdoctoral Research Associate at St. Jude Children’s Res. Hosp.

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 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. 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 without limiting effector differentiation. Extending this Tpex-preserving mechanism to tumor immunotherapy, we demonstrate that Asxl1 disruption in T cells mediates superior therapeutic efficacy in historically suppressive tumor microenvironments and is coupled to longer survival of patients treated with anti-PD-L1. 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.