Background Acute Myeloid Leukemia (AML) is the most common adult leukemia and has a very poor prognosis. With a 5-year survival of under 30% (seer.cancer.gov), most people diagnosed with AML will die from the disease. AML is caused by an uncontrolled proliferation of poorly differentiated myeloid precursor cells which results from a combination of three classes of mutations that affect proliferation, differentiation and epigenetic state. For this reason, drugs targeting epigenetic modifications are being actively studied in AML. AML has been shown to avoid immune recognition though inhibiting the function of multiple cell types, especially T cells1 2 and therefore immune checkpoint blockade presents a promising therapy for any immune-targeted strategy; however, clinical trials to date have shown very modest efficacy.3–5 T cell exhaustion in cancer has been shown to be a regulated process involving transcriptional and epigenetic changes.6–9 BRD4 has been shown to be important for maintaining this exhaustion state.10 11 It stands to reason that drugs designed to target epigenetic pathways in tumors will have effects on T cell populations present in the tumor microenvironment. 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.
Methods The AML mouse model bears FLT3-ITD and deletion of TET2 restricted to the myeloid lineage. For in vitro studies, splenocytes were stimulated with anti-CD3 and either JQ1, anti-PD1 or both and proliferation and differentiation status were assessed by flow cytometry. For in vivo studies, treatment consisted of 2 weeks with JQ1, anti-PD1 or both.
Results This mouse model of AML exhibits an expansion of terminally exhausted T cells and impaired proliferative capacity after stimulation through the TCR (figure 1). 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 (TPEx-CD8, PD1+, TCF1+, TIM3-) (figure 2). Finally, we show that BETi synergizes with anti-PD1 in vivo leading to a reduction of tumor cells in multiple organ sites, and enrichment of CD8+ T cells in the bone marrow (figure 3).
Conclusions Using an AML mouse model that exhibits leukemia-induced immune exhaustion, we demonstrate the pre-clinical efficacy of combining BETi and anti-PD1 therapy in the treatment of AML.
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