Epigenetic modulation enhances immunotherapy for pancreatic ductal adenocarcinoma
Abstract 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 ep...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2022-01-01
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| Series: | Clinical & Translational Immunology |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/cti2.1430 |
| _version_ | 1797976212355678208 |
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| author | Yan Li Young K Hong Xingtong Wang Harshul Pandit Qianqian Zheng Youxi Yu Xiaoju Shi Yujia Chen Min Tan Zachary Pulliam Neal Bhutiani Andrew Lin Jeremy Badach Ping Zhang Robert CG Martin |
| author_facet | Yan Li Young K Hong Xingtong Wang Harshul Pandit Qianqian Zheng Youxi Yu Xiaoju Shi Yujia Chen Min Tan Zachary Pulliam Neal Bhutiani Andrew Lin Jeremy Badach Ping Zhang Robert CG Martin |
| author_sort | Yan Li |
| collection | DOAJ |
| description | Abstract 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 5μm 3‐Deazaneplanocin A (DZNep, an EZH2 inhibitor) and 5 μm 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. |
| first_indexed | 2024-04-11T04:47:29Z |
| format | Article |
| id | doaj.art-2b4fe68defad4b57a1bec3372df08b6d |
| institution | Directory Open Access Journal |
| issn | 2050-0068 |
| language | English |
| last_indexed | 2024-04-11T04:47:29Z |
| publishDate | 2022-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Clinical & Translational Immunology |
| spelling | doaj.art-2b4fe68defad4b57a1bec3372df08b6d2022-12-27T07:10:33ZengWileyClinical & Translational Immunology2050-00682022-01-011112n/an/a10.1002/cti2.1430Epigenetic modulation enhances immunotherapy for pancreatic ductal adenocarcinomaYan Li0Young K Hong1Xingtong Wang2Harshul Pandit3Qianqian Zheng4Youxi Yu5Xiaoju Shi6Yujia Chen7Min Tan8Zachary Pulliam9Neal Bhutiani10Andrew Lin11Jeremy Badach12Ping Zhang13Robert CG Martin14Division of Surgical Oncology, Hiram C. Polk Jr., M.D. Department of Surgery School of Medicine, University of Louisville Louisville KY USADivision of Surgical Oncology, Hiram C. Polk Jr., M.D. Department of Surgery School of Medicine, University of Louisville Louisville KY USADivision of Surgical Oncology, Hiram C. Polk Jr., M.D. Department of Surgery School of Medicine, University of Louisville Louisville KY USADivision of Surgical Oncology, Hiram C. Polk Jr., M.D. Department of Surgery School of Medicine, University of Louisville Louisville KY USADivision of Surgical Oncology, Hiram C. Polk Jr., M.D. Department of Surgery School of Medicine, University of Louisville Louisville KY USADivision of Surgical Oncology, Hiram C. Polk Jr., M.D. Department of Surgery School of Medicine, University of Louisville Louisville KY USADivision of Surgical Oncology, Hiram C. Polk Jr., M.D. Department of Surgery School of Medicine, University of Louisville Louisville KY USADivision of Surgical Oncology, Hiram C. Polk Jr., M.D. Department of Surgery School of Medicine, University of Louisville Louisville KY USADivision of Surgical Oncology, Hiram C. Polk Jr., M.D. Department of Surgery School of Medicine, University of Louisville Louisville KY USADivision of Surgical Oncology, Hiram C. Polk Jr., M.D. Department of Surgery School of Medicine, University of Louisville Louisville KY USADivision of Surgical Oncology, Hiram C. Polk Jr., M.D. Department of Surgery School of Medicine, University of Louisville Louisville KY USADivision of Surgical Oncology, Department of Surgery Cooper University Hospital Camden NJ USADivision of Surgical Oncology, Department of Surgery Cooper University Hospital Camden NJ USADivision of Surgical Oncology, Department of Surgery Cooper University Hospital Camden NJ USADivision of Surgical Oncology, Hiram C. Polk Jr., M.D. Department of Surgery School of Medicine, University of Louisville Louisville KY USAAbstract 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 5μm 3‐Deazaneplanocin A (DZNep, an EZH2 inhibitor) and 5 μm 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.https://doi.org/10.1002/cti2.1430checkpoint inhibitorsepigenetic modulationimmunotherapypancreatic ductal adenocarcinoma (PDAC) |
| spellingShingle | Yan Li Young K Hong Xingtong Wang Harshul Pandit Qianqian Zheng Youxi Yu Xiaoju Shi Yujia Chen Min Tan Zachary Pulliam Neal Bhutiani Andrew Lin Jeremy Badach Ping Zhang Robert CG Martin Epigenetic modulation enhances immunotherapy for pancreatic ductal adenocarcinoma Clinical & Translational Immunology checkpoint inhibitors epigenetic modulation immunotherapy pancreatic ductal adenocarcinoma (PDAC) |
| title | Epigenetic modulation enhances immunotherapy for pancreatic ductal adenocarcinoma |
| title_full | Epigenetic modulation enhances immunotherapy for pancreatic ductal adenocarcinoma |
| title_fullStr | Epigenetic modulation enhances immunotherapy for pancreatic ductal adenocarcinoma |
| title_full_unstemmed | Epigenetic modulation enhances immunotherapy for pancreatic ductal adenocarcinoma |
| title_short | Epigenetic modulation enhances immunotherapy for pancreatic ductal adenocarcinoma |
| title_sort | epigenetic modulation enhances immunotherapy for pancreatic ductal adenocarcinoma |
| topic | checkpoint inhibitors epigenetic modulation immunotherapy pancreatic ductal adenocarcinoma (PDAC) |
| url | https://doi.org/10.1002/cti2.1430 |
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