PMID- 36452477 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20230124 IS - 2050-0068 (Print) IS - 2050-0068 (Electronic) IS - 2050-0068 (Linking) VI - 11 IP - 12 DP - 2022 TI - Epigenetic modulation enhances immunotherapy for pancreatic ductal adenocarcinoma. PG - e1430 LID - 10.1002/cti2.1430 [doi] LID - e1430 AB - OBJECTIVES: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a poor prognosis. PDAC has poor response to immunotherapy because of its unique tumour microenvironment (TME). In an attempt to stimulate immunologically silent pancreatic cancer, we investigated the role of epigenetic therapy in modulating the TME to improve immunogenicity. METHODS: In vitro human PDAC cell lines MiaPaca2 and S2-013 were treated with 5mu m 3-Deazaneplanocin A (DZNep, an EZH2 inhibitor) and 5 mu m 5-Azacytidine (5-AZA, a DNMT1 inhibitor). In vivo orthotopic murine tumour models using both murine PAN02 cells and KPC cells inoculated in immunocompetent C56/BL7 mice were treated with anti-PD-L1 combined with DZNep and 5-AZA. Short hairpin knockdown (KD) of EZH2 and DNMT1 in PAN02 cells for the orthotopic murine tumour model was established to validate the drug treatment (DZNep and 5-AZA). qRT-PCR and microarray assays were performed for the evaluation of Th1-attracting chemokines and cancer-associated antigen induction. RESULTS: Drug treatments induced significant upregulation of gene expressions of Th1-attracting chemokines, CXCL9 and CXCL10, and the cancer-testis antigens, NY-ESO-1, LAGE and SSX-4 (P < 0.05). In orthotopic tumour models, inoculation of PAN02 cells or KPC cells demonstrated significant tumour regression with corresponding increased apoptosis and infiltration of cytotoxic T lymphocytes in the combination treatment group. In the orthotopic Pan02-KD model, the anti-PD-L1 treatment also caused significant tumour regression. CONCLUSION: We demonstrate that immunotherapy for PDAC can be potentiated with epigenetic therapy by increasing cancer-associated antigen expression and increased T-cell trafficking across the immunosuppressive tumour microenvironment via upregulation of the repressed chemokines and increased apoptosis with subsequent tumour regression. CI - (c) 2022 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd, on behalf of Australian and New Zealand Society for Immunology, Inc. FAU - Li, Yan AU - Li Y AD - Division of Surgical Oncology, Hiram C. Polk Jr., M.D. Department of Surgery School of Medicine, University of Louisville Louisville KY USA. AD - Department of Pharmacology & Toxicology University of Louisville School of Medicine Louisville KY USA. FAU - Hong, Young K AU - Hong YK AD - Division of Surgical Oncology, Hiram C. Polk Jr., M.D. Department of Surgery School of Medicine, University of Louisville Louisville KY USA. AD - Division of Surgical Oncology, Department of Surgery Cooper University Hospital Camden NJ USA. FAU - Wang, Xingtong AU - Wang X AD - Division of Surgical Oncology, Hiram C. Polk Jr., M.D. Department of Surgery School of Medicine, University of Louisville Louisville KY USA. AD - The First Hospital of Jilin University, Jilin University Changchun China. FAU - Pandit, Harshul AU - Pandit H AD - Division of Surgical Oncology, Hiram C. Polk Jr., M.D. Department of Surgery School of Medicine, University of Louisville Louisville KY USA. AD - Department of Pharmacology & Toxicology University of Louisville School of Medicine Louisville KY USA. FAU - Zheng, Qianqian AU - Zheng Q AUID- ORCID: 0000-0001-5906-148X AD - Division of Surgical Oncology, Hiram C. Polk Jr., M.D. Department of Surgery School of Medicine, University of Louisville Louisville KY USA. AD - Basic Medicine College, China Medical University Shenyang China. FAU - Yu, Youxi AU - Yu Y AD - Division of Surgical Oncology, Hiram C. Polk Jr., M.D. Department of Surgery School of Medicine, University of Louisville Louisville KY USA. AD - The First Hospital of Jilin University, Jilin University Changchun China. FAU - Shi, Xiaoju AU - Shi X AD - Division of Surgical Oncology, Hiram C. Polk Jr., M.D. Department of Surgery School of Medicine, University of Louisville Louisville KY USA. AD - The First Hospital of Jilin University, Jilin University Changchun China. FAU - Chen, Yujia AU - Chen Y AD - Division of Surgical Oncology, Hiram C. Polk Jr., M.D. Department of Surgery School of Medicine, University of Louisville Louisville KY USA. AD - The First Hospital of Jilin University, Jilin University Changchun China. FAU - Tan, Min AU - Tan M AD - Division of Surgical Oncology, Hiram C. Polk Jr., M.D. Department of Surgery School of Medicine, University of Louisville Louisville KY USA. FAU - Pulliam, Zachary AU - Pulliam Z AD - Division of Surgical Oncology, Hiram C. Polk Jr., M.D. Department of Surgery School of Medicine, University of Louisville Louisville KY USA. FAU - Bhutiani, Neal AU - Bhutiani N AD - Division of Surgical Oncology, Hiram C. Polk Jr., M.D. Department of Surgery School of Medicine, University of Louisville Louisville KY USA. FAU - Lin, Andrew AU - Lin A AD - Division of Surgical Oncology, Department of Surgery Cooper University Hospital Camden NJ USA. FAU - Badach, Jeremy AU - Badach J AD - Division of Surgical Oncology, Department of Surgery Cooper University Hospital Camden NJ USA. FAU - Zhang, Ping AU - Zhang P AD - Division of Surgical Oncology, Department of Surgery Cooper University Hospital Camden NJ USA. FAU - Martin, Robert Cg AU - Martin RC AUID- ORCID: 0000-0002-5537-3387 AD - Division of Surgical Oncology, Hiram C. Polk Jr., M.D. Department of Surgery School of Medicine, University of Louisville Louisville KY USA. AD - Department of Pharmacology & Toxicology University of Louisville School of Medicine Louisville KY USA. LA - eng GR - P20 GM113226/GM/NIGMS NIH HHS/United States PT - Journal Article DEP - 20221128 PL - Australia TA - Clin Transl Immunology JT - Clinical & translational immunology JID - 101638268 PMC - PMC9705274 OTO - NOTNLM OT - checkpoint inhibitors OT - epigenetic modulation OT - immunotherapy OT - pancreatic ductal adenocarcinoma (PDAC) COIS- The authors declare no conflict of interest. EDAT- 2022/12/02 06:00 MHDA- 2022/12/02 06:01 PMCR- 2022/11/28 CRDT- 2022/12/01 02:48 PHST- 2022/03/17 00:00 [received] PHST- 2022/07/19 00:00 [revised] PHST- 2022/10/21 00:00 [revised] PHST- 2022/10/27 00:00 [accepted] PHST- 2022/12/01 02:48 [entrez] PHST- 2022/12/02 06:00 [pubmed] PHST- 2022/12/02 06:01 [medline] PHST- 2022/11/28 00:00 [pmc-release] AID - CTI21430 [pii] AID - 10.1002/cti2.1430 [doi] PST - epublish SO - Clin Transl Immunology. 2022 Nov 28;11(12):e1430. doi: 10.1002/cti2.1430. eCollection 2022.