PacRim7 7th PacRim Meeting Poster Presentations (1) (52 abstracts)
Therapeutic targeting of Ezh2 enhances PD-1 blockade by induction of interferon gamma response
Anjali V Sheahan 1 , Katherine L Morel 1 , Deborah L Burkhart 1 , Nadia Boufaied 2 , Sukanya Panja 3 , Carla Calagua 4 , Ying Huang 1 , Huihui Ye 4 , Shana Y Trostel 5 , Nichelle C Whitlock 5 , Scott Wilkinson 5 , Adam G Sowalsky 5 , Adam S Kibel 6 , Massimo Loda 1, , Christopher J Sweeney 9 , Antonina Mitrofanova 3 , Stephanie K Dougan 10 , David P Labbé 2 , Brian M Olson 11 & Leigh Ellis 1,
1Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; 2Division of Urology, Department of Surgery, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada; 3Department of Health Informatics, Rutgers School of Health Professions, Rutgers Biomedical and Health Sciences, Newark, NJ, USA; 4Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA; 5Laboratory of Genitourinary Cancer Pathogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA; 6Department of Urology, Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; 7Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; 8The Broad Institute, Cambridge, MA, USA; 9Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; 10Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; 11Department of Hematology and Medical Oncology, and Department of Urology, Emory University, Atlanta, GA, USA.
Prostate cancers are considered immunologically ‘cold’ tumors as they demonstrate poor response to check-point inhibitor therapy (CPI). Enrichment of interferon gamma (IFNγ) response genes, critical for innate and adaptive immune response to viral infections, have been demonstrated to indicate a positive response to CPI. Tumor IFNγ signaling acts as both an activator and inhibitor of effector T-cell response/trafficking via regulation of Th-1 chemokines (CXCL9/10), and immune checkpoints (PD-L1 and PD-1). Enhancer of zeste homolog-2 (EZH2) is a histone methyltransferase that mediates gene repression, is commonly over-expressed in prostate cancer and is known to negative regulate IFN response genes. With this, we hypothesized that inhibition of EZH2 would induce IFN gene response and potentiate prostate tumor response to CPI. EZH2 inhibition of 3D prostate tumor organoids significantly induced double-strand RNA and PD-L1 expression, and IFN response gene signatures. Generation of a novel EZH2 repression signature (EZH2_RS) was used to segregate prostate cancer patients, from three independent clinical cohorts, based on EZH2 activity. Correlation analysis confirmed that tumors with low EZH2 function had increased enrichment of IFNγ response and Th1 immune cell infiltration gene signatures, and PD-L1 gene expression. By employing a mixed lymphocytic reaction assay, we demonstrated that EZH2 inhibition significantly repressed splenocyte-mediated cytotoxic tumor elimination, which is rescued upon CPI. In vivo, the combination of EZH2 inhibition and CPI significantly slowed prostate tumor growth compared to control and single therapy arms. Collectively, our findings indicate EZH2 mediates prostate cancer immune evasion and its subsequent inhibition enables CPI response. This data provides strong rationale for further clinical development of this combination strategy for the treatment of prostate cancer.
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Oncology Abstracts
ISSN 2631-4657 (online)
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