BET inhibitors synergize with anti-PD1 by rescuing TCF1+ progenitor exhausted CD8+ T cells in Acute Myeloid Leukemia
Cold Spring Harbor Laboratory, 2021
Online
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Zugriff:
Many acute myeloid leukemia (AML) patients exhibit hallmarks of immune exhaustion, such as increased myeloid derived suppressor cells (MDSCs), suppressive regulatory T cells (Tregs) and dysfunctional T cells. We have developed a mouse model of AML driven by Flt3-ITD and Tet2 deficiency displays these immune-related features, including CD8+ T cells exhibiting a terminally exhausted phenotype (TEx). This T cell subset has been shown to be refractory to immune checkpoint blockade (ICB) monotherapy. Here we show that small molecule inhibitors which target bromodomain and extra-terminal domain (BET) proteins affect both 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 (TPEx). This reversal is enhanced by combined BETi and anti-PD1 treatment. 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 expression of Tcf7, Slamf6, and Cxcr5 in CD8+ T cells. In total, we show the potential efficacy of combining BETi and ICB therapy in the treatment of AML.
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BET inhibitors synergize with anti-PD1 by rescuing TCF1+ progenitor exhausted CD8+ T cells in Acute Myeloid Leukemia
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Autor/in / Beteiligte Person: | Newman, Matthew T. ; Scott, Jaime ; Lind, Evan F. ; Coy, Jesse L. ; Cho, Hyun-jun ; Byrd, Kaelan ; Loo, Christopher P. ; Romine, Kyle A. ; Flynn, Patrick A. ; Kosaka, Yoko |
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Veröffentlichung: | Cold Spring Harbor Laboratory, 2021 |
Medientyp: | unknown |
DOI: | 10.1101/2021.08.04.455147 |
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