BET inhibitors synergize with anti-PD1 by rescuing TCF1+ progenitor exhausted CD8+ T cells in Acute Myeloid Leukemia

Abstract Many AML patients exhibit hallmarks of immune exhaustion such as increased myeloid derived suppressor cells (MDSCs), suppressive regulatory T cells (Tregs), and exhausted/dysfunctional T cells. We developed an AML mouse model driven by FLT3-ITD and TET2 deficiency to evaluate the immune effects of small-molecule inhibitors (SMIs) and immune checkpoint blockade (ICB). This mouse model recapitulated immune-related features in AML patients, such as increased myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs). Moreover, we found that CD8+ T cells derived from these mice exhibit a terminally exhausted phenotype (TEx PD1+, TIM3+, TCF1-), which have been shown to be refractory to ICB monotherapy. Here we show that SMIs targeting Bromodomain and Extra-Terminal (BET) proteins, in addition to targeting tumor-intrinsic factors, rescue T cell exhaustion and ICB resistance. Ex vivo treatment of splenocytes from these mice with BET inhibitors (BETi) reversed CD8+ T cell exhaustion by restoring proliferative capacity and expanding the more functional precursor exhausted T cells (TPEx: PD1+, TCF1+, TIM3-). This reversal is even more pronounced with BETi in combination with anti-PD1. Finally, we show that BETi synergizes with anti-PD1 in vivo, resulting in the reduction of circulating leukemia cells, enrichment of CD8+ T cells in the bone marrow and increased TPEx CD8+ T cells. In total, we employ an AML mouse model that is characterized by leukemia-induced immune exhaustion to show the potential efficacy of combining BETi and ICB therapy in the treatment of AML.