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

Abstract

Acute Myeloid Leukemia (AML) is the most common adult leukemia and has a 5-year survival of under 30%. AML is caused by uncontrolled proliferation of myeloid cells resulting from a combination of mutations that affect proliferation, differentiation and epigenetic state. For this reason, drugs targeting epigenetic modifications are being studied in AML. AML cells avoid immune recognition though inhibiting the function of multiple cell types, especially T cells and therefore immune checkpoint blockade presents a promising therapy; however, clinical trials to date have shown very modest efficacy. T cell exhaustion has been shown to be a regulated process involving transcriptional and epigenetic changes. BET proteins, which are chromatin readers, have been implicated in maintaining this exhaustion state. In these studies, we investigated the effects of the BET inhibitor (BETi) JQ1 on T cell exhaustion and checkpoint responsiveness in a murine model of AML and AML patient samples. The AML mouse model bears FLT3-ITD and deletion of TET2 restricted to myeloid lineages and is resistant to anti-PD1 therapy. This mouse model of AML expanded terminally exhausted T cells and impaired proliferative capacity after TCR stimulation. Ex vivo treatment with BETi and anti-PD1 reverses CD8+ T cell exhaustion via rescue of proliferative dysfunction and expansion of more functional precursor exhausted T cells in patient samples and AML splenocytes. Finally, we show that BETi rescues anti-PD1 resistance in vivo and reduces tumor burden in multiple organ sites and enriches CD8+ T cells in the bone marrow. In total, we demonstrate that combining BETi and anti-PD1 therapy in the treatment of AML is a rational strategy to overcome anti-PD1 resistance.