JQ1, a Selective Bromodomain Inhibitor, Augment the Immunogenicity of Mantle Cell Lymphoma By Influencing the Expression of PD-L1

Mantle cell lymphoma (MCL) is a rare and aggressive form of non-Hodgkin's B-cell lymphoma and represents 4% to 8% of NHL. New therapeutic strategies are under development to improve the clinical outcome of patients with this disease. Recent studies have highlighted the importance of BRD/acetyl-lysine binding in orchestrating molecular interactions in chromatin biology and regulating gene transcription. The Bromodomain (BRD) is a diverse family of evolutionary conserved protein-interaction modules, which recognizes acetylated lysine residues such as those on the N-terminal tails of histones.

We have recently determined the functional consequences of inhibiting Bromodomains in MCL. First, we evaluated the effects of JQ1, a selective small-molecule bromodomain inhibitor upon MCL's immunogenicity and antigen-specific CD4⁺ T-cell responses. In vitro treatment of MCL cells with increasing concentrations of JQ1 resulted in a decreased expression of the tolerogenic molecule PD-L1 as compared to control cells. Second, we evaluated the capabilities of JQ1-treated MCL cells to present cognate antigen to naïve or anergic antigen-specific CD4⁺ T-cells. We found that treatment of MCL cells with JQ1 enhances their antigen-presenting capabilities leading to effective priming of naïve CD4⁺ T-cells and restoring the responsiveness of tolerant T-cells as determined by their increased production of IL-2 and IFN-gamma in response to cognate antigen. More importantly, in vivo studies clearly demonstrated a strong anti-tumor effect in JQ1-treated MCL tumor bearing mice. Mechanistically, we found a decreased STAT3 phosphorylation and c-Myc expression in JQ1-treated MCL cells, which in turn might be responsible for the diminished expression of PDL1 and augmentation of MCL's immunogenicity.

Taken together, we have found that MCL cells treated with the Bromodomain specific inhibitor JQ1 are more inflammatory, display lower expression of the immunosuppressive molecule PDL1 and, are capable of restoring the responsiveness of tolerant T-cells. More importantly, JQ1 treatment in vivo inhibits tumor growth in MCL tumor bearing animals. Our studies therefore have unveiled a previously unknown immunological effect of BRD inhibitors and have identified a novel immunotherapeutic approach in MCL.