BET Protein Inhibition Relieves MDSC-Mediated Immune Suppression in Chronic Lymphocytic Leukemia

TL;DR

This study shows that inhibiting BET proteins, like BRD4, can reduce immune suppression caused by MDSCs in chronic lymphocytic leukemia.

Contribution

The novel finding is that BET inhibition reverses MDSC-mediated immune suppression in a mouse model of CLL.

Findings

MDSCs from leukemic mice show higher BRD4 expression and stronger immune suppression than those from healthy mice.

Ex vivo OPN5 treatment reduces MDSC immune suppression by enhancing T-cell function.

In vivo OPN5 treatment slows CLL progression and alters immune cell populations.

Abstract

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.

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.

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.

Altogether, these data support BET inhibition as a useful therapeutic approach to reverse MDSC-mediated immune suppression in CLL.

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