BET inhibitors rescue anti-PD1 resistance by enhancing TCF7 accessibility in leukemia-derived terminally exhausted CD8+ T cells

Abstract

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.

Leukemic mutation FLT3-ITD is retained in dendritic cells and disrupts their homeostasis leading to expanded Th17 frequency

“…To better understand how the FLT3-ITD mutation in AML affects cDCs, we characterized cDCs in a mouse model of AML. Our lab has previously published work using AML mice that harbor the FLT3-ITD mutation and spontaneously develop AML to interrogate T cell dysfunction [36, 37]. Here we utilized mice that express one copy of FLT3-ITD under the endogenous FLT3 promoter, have a homozygous loss of TET2 and a homozygous loss of p53 using Cre-mediated deletion of LoxP-flanked alleles (AML mice) [21, 27, 38, 39].…”

Tumor sialylation controls effective anti-cancer immunity in breast cancer

“…Consequently, abrogation of tumor sialylation facilitated CD8 + mediated tumor control and the recruitment of Tcf7 + CD8 + memory T cells within the TME. In multiple studies, Tcf7 + CD8 + memory T cells have been linked to ICI responses (15,16,(29)(30)(31)(32).…”

“…to immune checkpoint inhibitor responses (15,16,(29)(30)(31)(32). The interference with sialylation therefore resulted not only in prolonged control of the breast tumors but, most importantly, also in breaking the resistance of breast tumors to anti-PD1 therapy.…”

BETi – Are all BETs off in the clinic?

“…Whilst this in itself is of great interest, another study in AML found that BETi could effectively rescue both T cell exhaustion and immune cell blockade resistance. [ 5 ] The mechanism posited suggests that BETi act mechanistically to relieve the repression of progenitor programs in exhausted CD8+ T cells and restore and maintain a pool of anti‐PD1 responsive CD8+ T cells. [ 5 ] Indeed an earlier study in chronic lymphocytic leukaemia (CML), also found that BETi could reinvigorate exhausted T cells, [ 6 ] and moreover had potential applicability with respect to CD19‐targeted chimeric antigen receptor (CAR)‐T therapy.…”

“…[ 5 ] The mechanism posited suggests that BETi act mechanistically to relieve the repression of progenitor programs in exhausted CD8+ T cells and restore and maintain a pool of anti‐PD1 responsive CD8+ T cells. [ 5 ] Indeed an earlier study in chronic lymphocytic leukaemia (CML), also found that BETi could reinvigorate exhausted T cells, [ 6 ] and moreover had potential applicability with respect to CD19‐targeted chimeric antigen receptor (CAR)‐T therapy. In this study, the authors found that for a subset of patients who relapsed upon CAR‐T‐based therapy, BET proteins were associated with the loss of the CAR, and this loss could be subsequently relieved by the use of BETi.…”