Many acute myeloid leukemia (AML) patients exhibit hallmarks of immune exhaustion, such as increased myeloid-derived suppressor cells, suppressive regulatory T cells and dysfunctional T cells. Similarly, we have identified the same immune-related features, including exhausted CD8+ T cells (TEx) in a mouse model of AML. Here we show that inhibitors that target bromodomain and extra-terminal domain (BET) proteins affect tumor-intrinsic factors but also rescue T cell exhaustion and ICB resistance. Ex vivo treatment of cells from AML mice and AML patients with BET inhibitors (BETi) reversed CD8+ T cell exhaustion by restoring proliferative capacity and expansion of the more functional precursor-exhausted T cells. This reversal was enhanced by combined BETi and anti-PD1 treatment. BETi synergized with anti-PD1 in vivo, resulting in the reduction of circulating leukemia cells, enrichment of CD8+ T cells in the bone marrow, and increase in expression of Tcf7, Slamf6, and Cxcr5 in CD8+ T cells. Finally, we profiled the epigenomes of in vivo JQ1-treated AML-derived CD8+ T cells by single-cell ATAC-seq and found that JQ1 increases Tcf7 accessibility specifically in Tex cells, suggesting that BETi likely acts mechanistically by relieving repression of progenitor programs in Tex CD8+ T cells and maintaining a pool of anti-PD1 responsive CD8+ T cells.
Fifty-four consecutive patients with acute myeloid leukemia (AML) in first relapse presenting at a single institution were studied to determine factors affecting response to re-induction therapy. For purposes of analysis, re-treatment protocols were grouped into two categories, one with high dose and the other with standard dose cytosine arabinoside. Most regimens also included an anthracycline, mitoxantrone or amsacrine. Thirty-one of the 51 patients (61%) who received therapy achieved a second complete remission (CR-2). Median duration of CR-2 was 6 months (range 1-24+ months). Five patients remain in CR-2, three of whom received bone marrow transplants (median follow-up 24 months). The variables, age, gender, FAB subtype, leukocyte and platelet count, duration of CR-1, the initial and re-induction regimens were analyzed for prognostic value in attaining and maintaining CR-2. Only younger age (p < 0.001) and longer CR-1 duration (p < 0.05) were significantly correlated with greater likelihood of attaining CR-2 with univariate analysis, and only age was correlated with CR-2 rate using multivariate analysis (p = 0.018). Younger age was associated with longer CR-2 duration (p = 0.003) using multivariate analysis, a correlation that persisted when transplanted patients were excluded. There was no advantage to the use of high dose versus standard dose cytosine arabinoside in the reinduction regimen with respect to the ability to either achieve or sustain CR-2. Our data indicate that although the remission induction rate for AML in first relapse is high, remissions are brief and other strategies are required to improve outcome of patients in second remission.
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.
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.
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