Combination cancer immunotherapy targeting TNFR2 and PD-1/PD-L1 signaling reduces immunosuppressive effects in the microenvironment of pancreatic tumors
Backgrounds In advanced pancreatic ductal adenocarcinoma (PDAC), immune therapy, including immune checkpoint inhibitors, has limited efficacy, encouraging the study of combination therapy.Methods Tumor necrosis factor receptor 2 (TNFR2) was analyzed via immunohistochemistry, immunofluorescence, west...
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BMJ Publishing Group
2022-03-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/10/3/e003982.full |
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| author | Yi Duan Wen Chen Jian Xu Xiaoyu Zhang Xiaozhen Zhang Tingbo Liang Xueli Bai Mengyi Lao Hanshen Yang Muchun Li Honggang Ying Lihong He Kang Sun Chengxiang Guo Haitao Jiang |
| author_facet | Yi Duan Wen Chen Jian Xu Xiaoyu Zhang Xiaozhen Zhang Tingbo Liang Xueli Bai Mengyi Lao Hanshen Yang Muchun Li Honggang Ying Lihong He Kang Sun Chengxiang Guo Haitao Jiang |
| author_sort | Yi Duan |
| collection | DOAJ |
| description | Backgrounds In advanced pancreatic ductal adenocarcinoma (PDAC), immune therapy, including immune checkpoint inhibitors, has limited efficacy, encouraging the study of combination therapy.Methods Tumor necrosis factor receptor 2 (TNFR2) was analyzed via immunohistochemistry, immunofluorescence, western blotting, and ELISAs. The in vitro mechanism that TNFR2 regulates programmed cell death 1 ligand 1 (PD-L1) was investigated using immunofluorescence, immunohistochemistry, flow cytometry, western blotting, and chromatin immunoprecipitation (ChIP). In vivo efficacy and mechanistic studies, using C57BL/6 mice and nude mice with KPC cell-derived subcutaneous and orthotopic tumors, employed antibodies against TNFR2 and PD-L1. Survival curves were constructed for the orthotopic model and a genetically engineered PDAC model (LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1-Cre). Mass cytometry, immunohistochemistry, and flow cytometry analyzed local and systemic alterations in the immunophenotype.Results TNFR2 showed high expression and is a prognostic factor in CD8+ T cell-enriched pancreatic cancer. TNFR2 promotes tumorigenesis and progression of pancreatic cancer via dual effect: suppressing cancer immunogenicity and partially accelerating tumor growth. TNFR2 positivity correlated with PD-L1, and in vitro and in vivo, it could regulate the expression of PDL1 at the transcription level via the p65 NF-κB pathway. Combining anti-TNFR2 and PD-L1 antibodies eradicated tumors, prolonged overall survival in pancreatic cancer, and induced strong antitumor immune memory and secondary prevention by reducing the infiltration of Tregs and tumor-associated macrophages and inducing CD8+ T cell activation in the PDAC microenvironment. Finally, the antitumor immune response derived from combination therapy is mainly dependent on CD8+ T cells, partially dependent on CD4+ T cells, and independent of natural killer cells.Conclusions Anti-TNFR2 and anti-PD-L1 combination therapy eradicated tumors by inhibiting their growth, relieving tumor immunosuppression, and generating robust memory recall. |
| format | Article |
| id | doaj-art-58bbf2ed42e04e7f9fe0518d81c605b1 |
| institution | OA Journals |
| issn | 2051-1426 |
| language | English |
| publishDate | 2022-03-01 |
| publisher | BMJ Publishing Group |
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| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-58bbf2ed42e04e7f9fe0518d81c605b12025-08-20T02:11:30ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262022-03-0110310.1136/jitc-2021-003982Combination cancer immunotherapy targeting TNFR2 and PD-1/PD-L1 signaling reduces immunosuppressive effects in the microenvironment of pancreatic tumorsYi Duan0Wen Chen1Jian Xu2Xiaoyu Zhang3Xiaozhen Zhang4Tingbo Liang5Xueli Bai6Mengyi Lao7Hanshen Yang8Muchun Li9Honggang Ying10Lihong He11Kang Sun12Chengxiang Guo13Haitao Jiang14Department of Infectious Diseases, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China1 State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, Guangdong, ChinaDepartment of Rheumatology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, ChinaSchool of Public Health and Management, Wenzhou Medical University, Wenzhou, ChinaDepartment of Hepatobiliary and Pancreatic Surgery,the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China9The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China1 Department of Respiratory and Critical Care Medicine, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, ChinaDepartment of Hepatobiliary and Pancreatic Surgery,the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, ChinaDepartment of Hepatobiliary and Pancreatic Surgery,the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, ChinaDepartment of Hepatobiliary and Pancreatic Surgery,the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, ChinaDepartment of Hepatobiliary and Pancreatic Surgery,the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, ChinaDepartment of Hepatobiliary and Pancreatic Surgery,the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, ChinaICE Bioscience, Beijing, ChinaDepartment of Hepatobiliary and Pancreatic Surgery,the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, ChinaDepartment of Hepatobiliary and Pancreatic Surgery,the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, ChinaBackgrounds In advanced pancreatic ductal adenocarcinoma (PDAC), immune therapy, including immune checkpoint inhibitors, has limited efficacy, encouraging the study of combination therapy.Methods Tumor necrosis factor receptor 2 (TNFR2) was analyzed via immunohistochemistry, immunofluorescence, western blotting, and ELISAs. The in vitro mechanism that TNFR2 regulates programmed cell death 1 ligand 1 (PD-L1) was investigated using immunofluorescence, immunohistochemistry, flow cytometry, western blotting, and chromatin immunoprecipitation (ChIP). In vivo efficacy and mechanistic studies, using C57BL/6 mice and nude mice with KPC cell-derived subcutaneous and orthotopic tumors, employed antibodies against TNFR2 and PD-L1. Survival curves were constructed for the orthotopic model and a genetically engineered PDAC model (LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1-Cre). Mass cytometry, immunohistochemistry, and flow cytometry analyzed local and systemic alterations in the immunophenotype.Results TNFR2 showed high expression and is a prognostic factor in CD8+ T cell-enriched pancreatic cancer. TNFR2 promotes tumorigenesis and progression of pancreatic cancer via dual effect: suppressing cancer immunogenicity and partially accelerating tumor growth. TNFR2 positivity correlated with PD-L1, and in vitro and in vivo, it could regulate the expression of PDL1 at the transcription level via the p65 NF-κB pathway. Combining anti-TNFR2 and PD-L1 antibodies eradicated tumors, prolonged overall survival in pancreatic cancer, and induced strong antitumor immune memory and secondary prevention by reducing the infiltration of Tregs and tumor-associated macrophages and inducing CD8+ T cell activation in the PDAC microenvironment. Finally, the antitumor immune response derived from combination therapy is mainly dependent on CD8+ T cells, partially dependent on CD4+ T cells, and independent of natural killer cells.Conclusions Anti-TNFR2 and anti-PD-L1 combination therapy eradicated tumors by inhibiting their growth, relieving tumor immunosuppression, and generating robust memory recall.https://jitc.bmj.com/content/10/3/e003982.full |
| spellingShingle | Yi Duan Wen Chen Jian Xu Xiaoyu Zhang Xiaozhen Zhang Tingbo Liang Xueli Bai Mengyi Lao Hanshen Yang Muchun Li Honggang Ying Lihong He Kang Sun Chengxiang Guo Haitao Jiang Combination cancer immunotherapy targeting TNFR2 and PD-1/PD-L1 signaling reduces immunosuppressive effects in the microenvironment of pancreatic tumors Journal for ImmunoTherapy of Cancer |
| title | Combination cancer immunotherapy targeting TNFR2 and PD-1/PD-L1 signaling reduces immunosuppressive effects in the microenvironment of pancreatic tumors |
| title_full | Combination cancer immunotherapy targeting TNFR2 and PD-1/PD-L1 signaling reduces immunosuppressive effects in the microenvironment of pancreatic tumors |
| title_fullStr | Combination cancer immunotherapy targeting TNFR2 and PD-1/PD-L1 signaling reduces immunosuppressive effects in the microenvironment of pancreatic tumors |
| title_full_unstemmed | Combination cancer immunotherapy targeting TNFR2 and PD-1/PD-L1 signaling reduces immunosuppressive effects in the microenvironment of pancreatic tumors |
| title_short | Combination cancer immunotherapy targeting TNFR2 and PD-1/PD-L1 signaling reduces immunosuppressive effects in the microenvironment of pancreatic tumors |
| title_sort | combination cancer immunotherapy targeting tnfr2 and pd 1 pd l1 signaling reduces immunosuppressive effects in the microenvironment of pancreatic tumors |
| url | https://jitc.bmj.com/content/10/3/e003982.full |
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