Chimeric Antigen Receptor T Cells Targeting Integrin αvβ6 Expressed on Cholangiocarcinoma Cells
Cholangiocarcinoma (CCA) is a lethal bile duct cancer that responds poorly to current standard treatments. A new therapeutic approach is, therefore, urgently needed. Adoptive T cell transfer using chimeric antigen receptor (CAR) T cells is a new therapeutic modality with demonstrated efficacy in hem...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-03-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2021.657868/full |
| _version_ | 1818847013304795136 |
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| author | Nattaporn Phanthaphol Nattaporn Phanthaphol Chalermchai Somboonpatarakun Chalermchai Somboonpatarakun Kwanpirom Suwanchiwasiri Kwanpirom Suwanchiwasiri Thaweesak Chieochansin Thaweesak Chieochansin Jatuporn Sujjitjoon Jatuporn Sujjitjoon Sopit Wongkham Sopit Wongkham John Maher Mutita Junking Mutita Junking Pa-thai Yenchitsomanus Pa-thai Yenchitsomanus |
| author_facet | Nattaporn Phanthaphol Nattaporn Phanthaphol Chalermchai Somboonpatarakun Chalermchai Somboonpatarakun Kwanpirom Suwanchiwasiri Kwanpirom Suwanchiwasiri Thaweesak Chieochansin Thaweesak Chieochansin Jatuporn Sujjitjoon Jatuporn Sujjitjoon Sopit Wongkham Sopit Wongkham John Maher Mutita Junking Mutita Junking Pa-thai Yenchitsomanus Pa-thai Yenchitsomanus |
| author_sort | Nattaporn Phanthaphol |
| collection | DOAJ |
| description | Cholangiocarcinoma (CCA) is a lethal bile duct cancer that responds poorly to current standard treatments. A new therapeutic approach is, therefore, urgently needed. Adoptive T cell transfer using chimeric antigen receptor (CAR) T cells is a new therapeutic modality with demonstrated efficacy in hematologic malignancies. However, its efficacy against solid tumors is modest, and further intensive investigation continues. An important factor that influences the success of CAR T cell therapy is the selection of a target antigen that is highly expressed on cancer cells, but markedly less so in normal cells. Integrin αvβ6 is upregulated in several solid tumors, but is minimally expressed in normal epithelial cells, which suggests integrin αvβ6 as an attractive target antigen for CAR T cell immunotherapy in CCA. We investigated integrin αvβ6 expression in pathological tissue samples from patients with liver fluke-associated CCA. We then created CAR T cells targeting integrin αvβ6 and evaluated their anti-tumor activities against CCA cells. We found overexpression of the integrin αvβ6 protein in 23 of 30 (73.3%) CCA patient tissue samples. Significant association between high integrin αvβ6 expression and short survival time (p = 0.043) was also observed. Lentiviral constructs were engineered to encode CARs containing an integrin αvβ6-binding peptide (A20) derived from foot-and-mouth disease virus fused with a second-generation CD28/CD3ζ signaling domain (A20-2G CAR) or with a fourth-generation CD28/4-1BB/CD27/CD3ζ signaling domain (A20-4G CAR). The A20-2G and A20-4G CARs were highly expressed in primary human T cells transduced with the engineered lentiviruses, and they exhibited high levels of cytotoxicity against integrin αvβ6-positive CCA cells (p < 0.05). Interestingly, the A20-2G and A20-4G CAR T cells displayed anti-tumor function against integrin αvβ6-positive CCA tumor spheroids (p < 0.05). Upon specific antigen recognition, A20-4G CAR T cells produced a slightly lower level of IFN-γ, but exhibited higher proliferation than A20-2G CAR T cells. Thus, the A20-4G CAR T cells with lower level of cytokine production, but with higher proliferation represents a promising potential adoptive T cell therapy for integrin αvβ6-positive CCA. |
| first_indexed | 2024-12-19T05:54:42Z |
| format | Article |
| id | doaj.art-f6c634b6006f43acb60e2a58300c20a0 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-19T05:54:42Z |
| publishDate | 2021-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-f6c634b6006f43acb60e2a58300c20a02022-12-21T20:33:29ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2021-03-011110.3389/fonc.2021.657868657868Chimeric Antigen Receptor T Cells Targeting Integrin αvβ6 Expressed on Cholangiocarcinoma CellsNattaporn Phanthaphol0Nattaporn Phanthaphol1Chalermchai Somboonpatarakun2Chalermchai Somboonpatarakun3Kwanpirom Suwanchiwasiri4Kwanpirom Suwanchiwasiri5Thaweesak Chieochansin6Thaweesak Chieochansin7Jatuporn Sujjitjoon8Jatuporn Sujjitjoon9Sopit Wongkham10Sopit Wongkham11John Maher12Mutita Junking13Mutita Junking14Pa-thai Yenchitsomanus15Pa-thai Yenchitsomanus16Graduate Program in Immunology, Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, ThailandSiriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, ThailandSiriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, ThailandDivision of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, ThailandSiriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, ThailandMolecular Medicine Program, Multidisciplinary Unit, Faculty of Science, Mahidol University, Bangkok, ThailandSiriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, ThailandDivision of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, ThailandSiriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, ThailandDivision of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, ThailandDepartment of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, ThailandCholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, ThailandKing's College London, King's Health Partners Integrated Cancer Centre and Division of Cancer Studies, Guy's Hospital, London, United KingdomSiriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, ThailandDivision of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, ThailandSiriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, ThailandDivision of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, ThailandCholangiocarcinoma (CCA) is a lethal bile duct cancer that responds poorly to current standard treatments. A new therapeutic approach is, therefore, urgently needed. Adoptive T cell transfer using chimeric antigen receptor (CAR) T cells is a new therapeutic modality with demonstrated efficacy in hematologic malignancies. However, its efficacy against solid tumors is modest, and further intensive investigation continues. An important factor that influences the success of CAR T cell therapy is the selection of a target antigen that is highly expressed on cancer cells, but markedly less so in normal cells. Integrin αvβ6 is upregulated in several solid tumors, but is minimally expressed in normal epithelial cells, which suggests integrin αvβ6 as an attractive target antigen for CAR T cell immunotherapy in CCA. We investigated integrin αvβ6 expression in pathological tissue samples from patients with liver fluke-associated CCA. We then created CAR T cells targeting integrin αvβ6 and evaluated their anti-tumor activities against CCA cells. We found overexpression of the integrin αvβ6 protein in 23 of 30 (73.3%) CCA patient tissue samples. Significant association between high integrin αvβ6 expression and short survival time (p = 0.043) was also observed. Lentiviral constructs were engineered to encode CARs containing an integrin αvβ6-binding peptide (A20) derived from foot-and-mouth disease virus fused with a second-generation CD28/CD3ζ signaling domain (A20-2G CAR) or with a fourth-generation CD28/4-1BB/CD27/CD3ζ signaling domain (A20-4G CAR). The A20-2G and A20-4G CARs were highly expressed in primary human T cells transduced with the engineered lentiviruses, and they exhibited high levels of cytotoxicity against integrin αvβ6-positive CCA cells (p < 0.05). Interestingly, the A20-2G and A20-4G CAR T cells displayed anti-tumor function against integrin αvβ6-positive CCA tumor spheroids (p < 0.05). Upon specific antigen recognition, A20-4G CAR T cells produced a slightly lower level of IFN-γ, but exhibited higher proliferation than A20-2G CAR T cells. Thus, the A20-4G CAR T cells with lower level of cytokine production, but with higher proliferation represents a promising potential adoptive T cell therapy for integrin αvβ6-positive CCA.https://www.frontiersin.org/articles/10.3389/fonc.2021.657868/fulladoptive T cell therapychimeric antigen receptorintegrin αvβ6immunotherapycholangiocarcinoma |
| spellingShingle | Nattaporn Phanthaphol Nattaporn Phanthaphol Chalermchai Somboonpatarakun Chalermchai Somboonpatarakun Kwanpirom Suwanchiwasiri Kwanpirom Suwanchiwasiri Thaweesak Chieochansin Thaweesak Chieochansin Jatuporn Sujjitjoon Jatuporn Sujjitjoon Sopit Wongkham Sopit Wongkham John Maher Mutita Junking Mutita Junking Pa-thai Yenchitsomanus Pa-thai Yenchitsomanus Chimeric Antigen Receptor T Cells Targeting Integrin αvβ6 Expressed on Cholangiocarcinoma Cells Frontiers in Oncology adoptive T cell therapy chimeric antigen receptor integrin αvβ6 immunotherapy cholangiocarcinoma |
| title | Chimeric Antigen Receptor T Cells Targeting Integrin αvβ6 Expressed on Cholangiocarcinoma Cells |
| title_full | Chimeric Antigen Receptor T Cells Targeting Integrin αvβ6 Expressed on Cholangiocarcinoma Cells |
| title_fullStr | Chimeric Antigen Receptor T Cells Targeting Integrin αvβ6 Expressed on Cholangiocarcinoma Cells |
| title_full_unstemmed | Chimeric Antigen Receptor T Cells Targeting Integrin αvβ6 Expressed on Cholangiocarcinoma Cells |
| title_short | Chimeric Antigen Receptor T Cells Targeting Integrin αvβ6 Expressed on Cholangiocarcinoma Cells |
| title_sort | chimeric antigen receptor t cells targeting integrin αvβ6 expressed on cholangiocarcinoma cells |
| topic | adoptive T cell therapy chimeric antigen receptor integrin αvβ6 immunotherapy cholangiocarcinoma |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2021.657868/full |
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