PLAP -CAR Tcells mediate high specific cytotoxicity against colon cancer cells
Placental alkaline phosphatase, PLAP encoded by ALPP gene in humans is mainly expressed in placenta and testis, and not expressed in any other normal tissues. PLAP is overexpressed in colorectal cancers which makes it an attractive target for CAR (chimeric antigen receptor)-T cell therapy. PLAP mRNA...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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IMR Press
2020-06-01
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| Series: | Frontiers in Bioscience-Landmark |
| Subjects: | |
| Online Access: | https://www.imrpress.com/journal/FBL/25/9/10.2741/4877 |
| _version_ | 1828385570191048704 |
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| author | Xin Li Robert Berahovich Hua Zhou Xianghong Liu Feng Li Shirley Xu Yuehua Wei Djamila Ouaret Walter Bodmer Lijun Wu Vita Golubovskaya |
| author_facet | Xin Li Robert Berahovich Hua Zhou Xianghong Liu Feng Li Shirley Xu Yuehua Wei Djamila Ouaret Walter Bodmer Lijun Wu Vita Golubovskaya |
| author_sort | Xin Li |
| collection | DOAJ |
| description | Placental alkaline phosphatase, PLAP encoded by ALPP gene in humans is mainly expressed in placenta and testis, and not expressed in any other normal tissues. PLAP is overexpressed in colorectal cancers which makes it an attractive target for CAR (chimeric antigen receptor)-T cell therapy. PLAP mRNA expression was detected in 21.5% (25 out of 116) of colorectal cancer cell lines and this expression was confirmed by FACS at the protein level. In addition, IHC staining on primary colorectal cancer tumors demonstrated PLAP expression in >20% of colorectal cancer tumors. We generated mouse and humanized PLAP ScFv-CAR-T cells and demonstrated high specificity against PLAP-positive colon cancer cells using RTCA (real-time cytotoxicity assay) and IFN-gamma secretion. In addition, humanized-CAR-T cells significantly decreased Lovo xenograft tumor growth in vivo. The combination of hPLAP-CAR-T cells with PD-1, PD-L1 or LAG-3 checkpoint inhibitors significantly increased the activity of hPLAP-CAR-T cells. This study demonstrates ability of novel PLAP-CAR-T cells to kill colorectal cancers and that the extent of killing can be increased by combination with checkpoint inhibitors. |
| first_indexed | 2024-12-10T05:22:23Z |
| format | Article |
| id | doaj.art-5bfdc71ff5d94eb9bc0e7c838cc4f713 |
| institution | Directory Open Access Journal |
| issn | 2768-6701 |
| language | English |
| last_indexed | 2024-12-10T05:22:23Z |
| publishDate | 2020-06-01 |
| publisher | IMR Press |
| record_format | Article |
| series | Frontiers in Bioscience-Landmark |
| spelling | doaj.art-5bfdc71ff5d94eb9bc0e7c838cc4f7132022-12-22T02:00:47ZengIMR PressFrontiers in Bioscience-Landmark2768-67012020-06-012591765178610.2741/4877S2768-6701(20)00145-8PLAP -CAR Tcells mediate high specific cytotoxicity against colon cancer cellsXin Li0Robert Berahovich1Hua Zhou2Xianghong Liu3Feng Li4Shirley Xu5Yuehua Wei6Djamila Ouaret7Walter Bodmer8Lijun Wu9Vita Golubovskaya10Department of Hematology, The Third Xiangya Hospital, Central South University, Changsha 410013, PR ChinaPromab Biotechnologies, 2600 Hilltop Drive, Richmond, CA, 94806, USAPromab Biotechnologies, 2600 Hilltop Drive, Richmond, CA, 94806, USAPromab Biotechnologies, 2600 Hilltop Drive, Richmond, CA, 94806, USAPromab Biotechnologies, 2600 Hilltop Drive, Richmond, CA, 94806, USAPromab Biotechnologies, 2600 Hilltop Drive, Richmond, CA, 94806, USAPromab Biotechnologies, 2600 Hilltop Drive, Richmond, CA, 94806, USACancer and Immunogenetics Laboratory, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK, OV3 9DSCancer and Immunogenetics Laboratory, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK, OV3 9DSPromab Biotechnologies, 2600 Hilltop Drive, Richmond, CA, 94806, USAPromab Biotechnologies, 2600 Hilltop Drive, Richmond, CA, 94806, USAPlacental alkaline phosphatase, PLAP encoded by ALPP gene in humans is mainly expressed in placenta and testis, and not expressed in any other normal tissues. PLAP is overexpressed in colorectal cancers which makes it an attractive target for CAR (chimeric antigen receptor)-T cell therapy. PLAP mRNA expression was detected in 21.5% (25 out of 116) of colorectal cancer cell lines and this expression was confirmed by FACS at the protein level. In addition, IHC staining on primary colorectal cancer tumors demonstrated PLAP expression in >20% of colorectal cancer tumors. We generated mouse and humanized PLAP ScFv-CAR-T cells and demonstrated high specificity against PLAP-positive colon cancer cells using RTCA (real-time cytotoxicity assay) and IFN-gamma secretion. In addition, humanized-CAR-T cells significantly decreased Lovo xenograft tumor growth in vivo. The combination of hPLAP-CAR-T cells with PD-1, PD-L1 or LAG-3 checkpoint inhibitors significantly increased the activity of hPLAP-CAR-T cells. This study demonstrates ability of novel PLAP-CAR-T cells to kill colorectal cancers and that the extent of killing can be increased by combination with checkpoint inhibitors.https://www.imrpress.com/journal/FBL/25/9/10.2741/4877chimeric antigen receptorimmunotherapycancerplapcheckpoint inhibitor |
| spellingShingle | Xin Li Robert Berahovich Hua Zhou Xianghong Liu Feng Li Shirley Xu Yuehua Wei Djamila Ouaret Walter Bodmer Lijun Wu Vita Golubovskaya PLAP -CAR Tcells mediate high specific cytotoxicity against colon cancer cells Frontiers in Bioscience-Landmark chimeric antigen receptor immunotherapy cancer plap checkpoint inhibitor |
| title | PLAP -CAR Tcells mediate high specific cytotoxicity against colon cancer cells |
| title_full | PLAP -CAR Tcells mediate high specific cytotoxicity against colon cancer cells |
| title_fullStr | PLAP -CAR Tcells mediate high specific cytotoxicity against colon cancer cells |
| title_full_unstemmed | PLAP -CAR Tcells mediate high specific cytotoxicity against colon cancer cells |
| title_short | PLAP -CAR Tcells mediate high specific cytotoxicity against colon cancer cells |
| title_sort | plap car tcells mediate high specific cytotoxicity against colon cancer cells |
| topic | chimeric antigen receptor immunotherapy cancer plap checkpoint inhibitor |
| url | https://www.imrpress.com/journal/FBL/25/9/10.2741/4877 |
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