Combination gemcitabine and PD-L1xCD3 bispecific T cell engager (BiTE) enhances T lymphocyte cytotoxicity against cholangiocarcinoma cells
Abstract Cholangiocarcinoma (CCA) is a lethal cancer with rapid progression and poor survival. Novel and more effective therapies than those currently available are, therefore, urgently needed. Our research group previously reported the combination of gemcitabine and cytotoxic T lymphocytes to be mo...
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Nature Portfolio
2022-04-01
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| Online Access: | https://doi.org/10.1038/s41598-022-09964-6 |
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| author | Methi Wathikthinnakon Piriya Luangwattananun Nunghathai Sawasdee Chutipa Chiawpanit Vannajan Sanghiran Lee Piyarat Nimmanpipug Yingmanee Tragoolpua Siriphorn Rotarayanont Thanich Sangsuwannukul Nattaporn Phanthaphol Yupanun Wutti-in Chalermchai Somboonpatarakun Thaweesak Chieochansin Mutita Junking Jatuporn Sujjitjoon Pa-thai Yenchitsomanus Aussara Panya |
| author_facet | Methi Wathikthinnakon Piriya Luangwattananun Nunghathai Sawasdee Chutipa Chiawpanit Vannajan Sanghiran Lee Piyarat Nimmanpipug Yingmanee Tragoolpua Siriphorn Rotarayanont Thanich Sangsuwannukul Nattaporn Phanthaphol Yupanun Wutti-in Chalermchai Somboonpatarakun Thaweesak Chieochansin Mutita Junking Jatuporn Sujjitjoon Pa-thai Yenchitsomanus Aussara Panya |
| author_sort | Methi Wathikthinnakon |
| collection | DOAJ |
| description | Abstract Cholangiocarcinoma (CCA) is a lethal cancer with rapid progression and poor survival. Novel and more effective therapies than those currently available are, therefore, urgently needed. Our research group previously reported the combination of gemcitabine and cytotoxic T lymphocytes to be more effective than single-agent treatment for the elimination of CCA cells. However, gemcitabine treatment of CCA cells upregulates the expression of an immune checkpoint protein (programmed death-ligand 1 [PD-L1]) that consequently inhibits the cytotoxicity of T lymphocytes. To overcome this challenge and take advantage of PD-L1 upregulation upon gemcitabine treatment, we generated recombinant PD-L1xCD3 bispecific T cell engagers (BiTEs) to simultaneously block PD-1/PD-L1 signaling and recruit T lymphocytes to eliminate CCA cells. Two recombinant PD-L1xCD3 BiTEs (mBiTE and sBiTE contain anti-PD-L1 scFv region from atezolizumab and from a published sequence, respectively) were able to specifically bind to both CD3 on T lymphocytes, and to PD-L1 overexpressed after gemcitabine treatment on CCA (KKU213A, KKU055, and KKU100) cells. mBiTE and sBiTE significantly enhanced T lymphocyte cytotoxicity against CCA cells, especially after gemcitabine treatment, and their magnitudes of cytotoxicity were positively associated with the levels of PD-L1 expression. Our findings suggest combination gemcitabine and PD-L1xCD3 BiTE as a potential alternative therapy for CCA. |
| format | Article |
| id | doaj-art-c30fc759386341b294deabee9dff6509 |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2022-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-c30fc759386341b294deabee9dff65092025-02-09T12:38:26ZengNature PortfolioScientific Reports2045-23222022-04-0112111510.1038/s41598-022-09964-6Combination gemcitabine and PD-L1xCD3 bispecific T cell engager (BiTE) enhances T lymphocyte cytotoxicity against cholangiocarcinoma cellsMethi Wathikthinnakon0Piriya Luangwattananun1Nunghathai Sawasdee2Chutipa Chiawpanit3Vannajan Sanghiran Lee4Piyarat Nimmanpipug5Yingmanee Tragoolpua6Siriphorn Rotarayanont7Thanich Sangsuwannukul8Nattaporn Phanthaphol9Yupanun Wutti-in10Chalermchai Somboonpatarakun11Thaweesak Chieochansin12Mutita Junking13Jatuporn Sujjitjoon14Pa-thai Yenchitsomanus15Aussara Panya16Doctoral Program in Biology, Faculty of Science, Chiang Mai UniversityDivision of Molecular Medicine, Department of Research and Development, Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol UniversityDivision of Molecular Medicine, Department of Research and Development, Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol UniversityDoctoral Program in Biology, Faculty of Science, Chiang Mai UniversityDepartment of Chemistry, Faculty of Science, University of MalayaDepartment of Chemistry, Faculty of Science, Chiang Mai UniversityDepartment of Biology, Faculty of Science, Chiang Mai UniversityDepartment of Biology, Faculty of Science, Chiang Mai UniversityDivision of Molecular Medicine, Department of Research and Development, Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol UniversityDivision of Molecular Medicine, Department of Research and Development, Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol UniversityDivision of Molecular Medicine, Department of Research and Development, Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol UniversityDivision of Molecular Medicine, Department of Research and Development, Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol UniversityDivision of Molecular Medicine, Department of Research and Development, Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol UniversityDivision of Molecular Medicine, Department of Research and Development, Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol UniversityDivision of Molecular Medicine, Department of Research and Development, Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol UniversityDivision of Molecular Medicine, Department of Research and Development, Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol UniversityDepartment of Biology, Faculty of Science, Chiang Mai UniversityAbstract Cholangiocarcinoma (CCA) is a lethal cancer with rapid progression and poor survival. Novel and more effective therapies than those currently available are, therefore, urgently needed. Our research group previously reported the combination of gemcitabine and cytotoxic T lymphocytes to be more effective than single-agent treatment for the elimination of CCA cells. However, gemcitabine treatment of CCA cells upregulates the expression of an immune checkpoint protein (programmed death-ligand 1 [PD-L1]) that consequently inhibits the cytotoxicity of T lymphocytes. To overcome this challenge and take advantage of PD-L1 upregulation upon gemcitabine treatment, we generated recombinant PD-L1xCD3 bispecific T cell engagers (BiTEs) to simultaneously block PD-1/PD-L1 signaling and recruit T lymphocytes to eliminate CCA cells. Two recombinant PD-L1xCD3 BiTEs (mBiTE and sBiTE contain anti-PD-L1 scFv region from atezolizumab and from a published sequence, respectively) were able to specifically bind to both CD3 on T lymphocytes, and to PD-L1 overexpressed after gemcitabine treatment on CCA (KKU213A, KKU055, and KKU100) cells. mBiTE and sBiTE significantly enhanced T lymphocyte cytotoxicity against CCA cells, especially after gemcitabine treatment, and their magnitudes of cytotoxicity were positively associated with the levels of PD-L1 expression. Our findings suggest combination gemcitabine and PD-L1xCD3 BiTE as a potential alternative therapy for CCA.https://doi.org/10.1038/s41598-022-09964-6 |
| spellingShingle | Methi Wathikthinnakon Piriya Luangwattananun Nunghathai Sawasdee Chutipa Chiawpanit Vannajan Sanghiran Lee Piyarat Nimmanpipug Yingmanee Tragoolpua Siriphorn Rotarayanont Thanich Sangsuwannukul Nattaporn Phanthaphol Yupanun Wutti-in Chalermchai Somboonpatarakun Thaweesak Chieochansin Mutita Junking Jatuporn Sujjitjoon Pa-thai Yenchitsomanus Aussara Panya Combination gemcitabine and PD-L1xCD3 bispecific T cell engager (BiTE) enhances T lymphocyte cytotoxicity against cholangiocarcinoma cells Scientific Reports |
| title | Combination gemcitabine and PD-L1xCD3 bispecific T cell engager (BiTE) enhances T lymphocyte cytotoxicity against cholangiocarcinoma cells |
| title_full | Combination gemcitabine and PD-L1xCD3 bispecific T cell engager (BiTE) enhances T lymphocyte cytotoxicity against cholangiocarcinoma cells |
| title_fullStr | Combination gemcitabine and PD-L1xCD3 bispecific T cell engager (BiTE) enhances T lymphocyte cytotoxicity against cholangiocarcinoma cells |
| title_full_unstemmed | Combination gemcitabine and PD-L1xCD3 bispecific T cell engager (BiTE) enhances T lymphocyte cytotoxicity against cholangiocarcinoma cells |
| title_short | Combination gemcitabine and PD-L1xCD3 bispecific T cell engager (BiTE) enhances T lymphocyte cytotoxicity against cholangiocarcinoma cells |
| title_sort | combination gemcitabine and pd l1xcd3 bispecific t cell engager bite enhances t lymphocyte cytotoxicity against cholangiocarcinoma cells |
| url | https://doi.org/10.1038/s41598-022-09964-6 |
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