BET Protein Inhibition Relieves MDSC-Mediated Immune Suppression in Chronic Lymphocytic Leukemia
Erin M Drengler1, Audrey L Smith1, Sydney A Skupa1
1Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Background:
Myeloid-derived suppressor cells (MDSCs) contribute to immune suppression observed in chronic lymphocytic leukemia (CLL). MDSCs are immature myeloid cells that are hijacked during development and further reprogrammed by the tumor microenvironment (TME) to harbor immune-suppressive properties and inhibit T-cell functions. Bromodomain and extraterminal domain (BET) proteins, including BRD4, are epigenetic modulators that regulate genes implicated in CLL pathogenesis and TME interactions. Previously, we investigated how the novel BET inhibitor OPN-51107 (OPN5) prevents CLL disease expansion, modulates T-cell immune function, and alters gene expression related to MDSCs. In turn, we hypothesize that BET proteins such as BRD4 regulate MDSC functions, and subsequent pharmacological inhibition of BRD4 will alleviate MDSC-mediated immune suppression in CLL.
Methods:
Utilizing the Eμ-TCL1 mouse model of CLL, we evaluated BRD4 protein expression in MDSCs derived from the bone marrow of transgenic and age-matched wild-type (WT) mice. We then investigated the ex vivo functionality of OPN5-treated MDSCs, expanded from Eμ-TCL1 and WT bone marrow in MDSC-supportive medium. Finally, we conducted an in vivo study utilizing the Eμ-TCL1 adoptive transfer mouse model to determine the in vivo effects of OPN5 on MDSCs and other immune populations.
Results:
Through the course of this study, we found that MDSCs isolated from Eμ-TCL1 mice upregulate BRD4 expression and are more immune-suppressive than their WT counterparts. Furthermore, we demonstrated ex vivo OPN5 treatment reverses the immune-suppressive capacity of MDSCs isolated from leukemic mice, evident via enhanced T-cell proliferation and IFNγ production. Finally, we showed in vivo OPN5 treatment slows CLL disease progression and modulates immune cell populations, including MDSCs.
Conclusions:
Altogether, these data support BET inhibition as a useful therapeutic approach to reverse MDSC-mediated immune suppression in CLL.
Related Concept Videos
02:23Abnormal Proliferation
01:15Receptor Downregulation in MVBs
The EGFR can initiate signaling pathways that lead to cell proliferation, migration, and differentiation. Overexpression of EGFR stimulates cells to proliferate. Excessive EGFR...