Using an AML mouse model that phenocopies immune exhaustion often found in AML patients, Romine et al. investigated if BET inhibitors (BETi) could restore checkpoint inhibitor responsiveness. BETi reversed CD8+ T cell exhaustion in ex vivo T cells from AML mice and patients by expanding proliferation of more functional anti-PD-1 responsive precursor exhausted T cells (TPEx), while decreasing non-responsive exhausted T cells (Tex). BETi synergized with anti-PD-1 in vivo, decreasing tumor burden and enriching CD8+ TPEx cells. ScATAC epigenetic profiling showed BETi increased Tcf7 accessibility in Tex cells, potentially rescuing anti-PD-1 resistance.
Contributed by Katherine Turner
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.
Author Info: (1) Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, OR, USA. (2) Department of Molecular & Medical Genetics, Oregon Health & Scien
Author Info: (1) Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, OR, USA. (2) Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR, USA. (3) Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, OR, USA. (4) Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, OR, USA. (5) Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, OR, USA. (6) Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, OR, USA. (7) Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, OR, USA. (8) School of Medicine, Oregon Health & Science University, Portland, OR, USA. (9) Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, OR, USA. (10) Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, OR, USA. (11) Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, OR, USA. (12) Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR, USA. Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA. Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR, USA. Center for Early Detection Advanced Research, Oregon Health & Science University, Portland, OR, USA. (13) Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, OR, USA. linde@ohsu.edu. Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, OR, USA. linde@ohsu.edu. Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA. linde@ohsu.edu.
