Immunogenicity of prostate cancer is augmented by BET bromodomain inhibition

Abstract

BackgroundProstate cancer responds poorly to current immunotherapies. Epigenetic therapies such as BET Bromodomain inhibition can change the transcriptome of tumor cells, possibly making them more immunogenic and thus susceptible to immune targeting.MethodsWe characterized the effects of BET bromodomain inhibition using JQ1 on PD-L1 and HLA-ABC expression in two human prostate cell lines, DU145 and PC3. RNA-Seq was performed to assess changes on a genome-wide level. A cytotoxic T cell killing assay was performed in MC38-OVA cells treated with JQ1 to demonstrate increased immunogenicity. In vivo experiments in the Myc-Cap model were conducted to show the effects of JQ1 administration in concert with anti-CTLA-4 checkpoint blockade.ResultsHere, we show that targeting BET bromodomains using the small molecule inhibitor JQ1 decreased PD-L1 expression and mitigated tumor progression in prostate cancer models. Mechanistically, BET bromodomain inhibition increased MHC I expression and increased the immunogenicity of tumor cells. Transcriptional profiling showed that BET bromodomain inhibition regulates distinct networks of antigen processing and immune checkpoint molecules. In murine models, treatment with JQ1 was additive with anti-CTLA-4 immunotherapy, resulting in an increased CD8/Treg ratio.ConclusionsBET Bromodomain inhibition can mediate changes in expression at a genome wide level in prostate cancer cells, resulting in an increased susceptibility to CD8 T cell targeting. These data suggest that combining BET bromodomain inhibition with immune checkpoint blockade may have clinical activity in prostate cancer patients.

Epigenetic Mechanisms of Resistance to Immune Checkpoint Inhibitors

“…Small molecule inhibitors, shown to act as immunomodulatory agents, have been developed and could be combined with immunotherapies to enhance response rates. In ovarian cancer, BRD4 inhibition was shown to reprogram tumor-infiltrating macrophages from the M2-type to M1-type, promoting proinflammatory cytokine secretion and the subsequent activation of CD8+ T cells [ 85 ], and, in prostate cancer, BRD4 inhibition was associated with an increased expression of MHC 1 genes by tumor cells, modification of the global gene expression with an activation of antigen-processing networks and an increased CD8+ T cells/Tregs ratio [ 86 ]. Altogether, many studies support the potential of BET inhibitors to promote antitumor immune responses.…”

“…In NSCLC, cooperative effects between JQ1 and the PD-1 antibody were found in mice models with a mutation of KRAS and deletion of TP53 [ 209 ]. The same molecule was used in a prostate cancer murine model, with similar conclusions [ 86 ]. However, BET inhibitors have, as a side effect, reversible neutropenia and thrombocytopenia [ 210 ].…”

Targeting the Immune system and Epigenetic Landscape of Urological Tumors

“…A summary of most recent studies addressing combination strategies between epigenetics and immune environment in PCa is depicted in Table 3 [108,[141][142][143][144][145][146][147][148][149][150][151][152]. Some studies have focused on epigenetic regulation of response to IFN, where both methylation and acetylation can be involved, as demonstrated by Dunn and collaborators [141].…”

“…Recently, among the epigenetic modifiers, those targeting bromodomains have been gathering some attention, including in PCa [153]. Mao et al has recently demonstrated that JQ1, an inhibitor of bromodomain and extra-terminal (BET) bromodomain family, impacts on the immune response players, including PD-L1 downregulation, MHC1 upregulation, additive effect to anti-CTLA-4 agents and inducing an increase in the CD8/Treg ratio, leading to immunogenicity [142].…”

Epitherapy and immune checkpoint blockade: using epigenetic reinvigoration of exhausted and dysfunctional T cells to reimburse immunotherapy response

“…Other epigenetics enzymes, such as the histone methyltransferase, EZH2, have been shown to regulate the expression of PD-L1 in hepatocellular carcinoma by upregulating H3K27me3 levels on the promoters of CD274 (encoding PD-L1) and IRF1 [40]. Furthermore, BET bromodomain inhibitors have been shown to upregulate PD-L1 and MHC I expression in ovarian and prostate cancer cells [41,42].…”