RT Journal Article
SR Electronic
T1 Targeting EZH2 Increases Therapeutic Efficacy of Check-Point Blockade in Models of Prostate Cancer
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 730135
DO 10.1101/730135
A1 Anjali V. Sheahan
A1 Katherine L. Morel
A1 Deborah L. Burkhart
A1 Sylvan C. Baca
A1 David P. Labbé
A1 Kevin Roehle
A1 Max Heckler
A1 Carla Calagua
A1 Huihui Ye
A1 Phillip Galbo
A1 Sukanya Panja
A1 Antonina Mitrofanova
A1 Anis A. Hamid
A1 Adam S. Kibel
A1 Atish D. Choudhury
A1 Mark M. Pomerantz
A1 Matthew L. Freedman
A1 Christopher J. Sweeney
A1 Stephanie K. Dougan
A1 Adam G. Sowalsky
A1 Massimo Loda
A1 Brian M. Olson
A1 Leigh Ellis
YR 2019
UL http://biorxiv.org/content/early/2019/08/08/730135.abstract
AB Prostate cancers are considered immunologically ‘cold’ tumors given the very few patients who respond to checkpoint inhibitor therapy (CPI). Recently, enrichment of interferon (IFN) response genes predicts a favorable response to CPI across various disease sites. The enhancer of zeste homolog-2 (EZH2) is over-expressed in prostate cancer and is known to negatively regulate IFN response genes. Here, we demonstrate that inhibition of EZH2 catalytic activity in prostate cancer models derepresses expression of double-strand RNA (dsRNA), associated with upregulation of genes involved in antigen presentation, Th-1 chemokine signaling, and interferon (IFN) response, including PD-L1. Similarly, application of a novel EZH2 derived gene signature to human prostate sample analysis indicated an inverse correlation between tumor EZH2 activity/expression with T-cell inflamed and IFN gene signatures and PD-L1 expression. EZH2 inhibition combined with PD-1 CPI significantly enhances antitumor response that is dependent on up-regulation of tumor PD-L1 expression. Further, combination therapy significantly increases intratumoral trafficking of activated CD8+ T-cells and M1 tumor associated macrophages (TAMs) with concurrent loss of M2 TAMs. Our study identifies EZH2 as a potent inhibitor of antitumor immunity and responsiveness to CPI. This data suggests EZH2 inhibition as a novel therapeutic direction to enhance prostate cancer response to PD-1 CPI.