Anti-mucin 1 chimeric antigen receptor T cells for adoptive T cell therapy of cholangiocarcinoma

Abstract Current treatments for cholangiocarcinoma (CCA) are largely unsuccessful due to late diagnosis at advanced stage, leading to high mortality rate. Consequently, improved therapeutic approaches are urgently needed. Chimeric antigen receptor (CAR) T cell therapy is a newly potential therapy th...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Kamonlapat Supimon, Thanich Sangsuwannukul, Jatuporn Sujjitjoon, Nattaporn Phanthaphol, Thaweesak Chieochansin, Naravat Poungvarin, Sopit Wongkham, Mutita Junking, Pa-thai Yenchitsomanus
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/5f4b108e3f6744c6a27402aa818b2f21
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:5f4b108e3f6744c6a27402aa818b2f21
record_format	dspace
spelling	oai:doaj.org-article:5f4b108e3f6744c6a27402aa818b2f212021-12-02T11:39:33ZAnti-mucin 1 chimeric antigen receptor T cells for adoptive T cell therapy of cholangiocarcinoma10.1038/s41598-021-85747-92045-2322https://doaj.org/article/5f4b108e3f6744c6a27402aa818b2f212021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-85747-9https://doaj.org/toc/2045-2322Abstract Current treatments for cholangiocarcinoma (CCA) are largely unsuccessful due to late diagnosis at advanced stage, leading to high mortality rate. Consequently, improved therapeutic approaches are urgently needed. Chimeric antigen receptor (CAR) T cell therapy is a newly potential therapy that can recognize specific surface antigen without major histocompatibility complex (MHC) restriction. Mucin 1 (MUC1) is an attractive candidate antigen as it is highly expressed and associated with poor prognosis and survival in CCA. We, therefore, set forth to create the fourth-generation CAR (CAR4) construct containing anti-MUC1-single-chain variable fragment (scFv) and three co-stimulatory domains (CD28, CD137, and CD27) linked to CD3ζ and evaluate anti-MUC1-CAR4 T cells in CCA models. Compared to untransduced T cells, anti-MUC1-CAR4 T cells produced increased levels of TNF-α, IFN-γ and granzyme B when exposed to MUC1-expressing KKU-100 and KKU-213A CCA cells (all p < 0.05). Anti-MUC1-CAR4 T cells demonstrated specific killing activity against KKU-100 (45.88 ± 7.45%, p < 0.05) and KKU-213A cells (66.03 ± 3.14%, p < 0.001) at an effector to target ratio of 5:1, but demonstrated negligible cytolytic activity against immortal cholangiocytes. Furthermore, the anti-MUC1-CAR4 T cells could effectively disrupt KKU-213A spheroids. These activities of anti-MUC1-CAR4 T cells supports the development of this approach as an adoptive T cell therapeutic strategy for CCA.Kamonlapat SupimonThanich SangsuwannukulJatuporn SujjitjoonNattaporn PhanthapholThaweesak ChieochansinNaravat PoungvarinSopit WongkhamMutita JunkingPa-thai YenchitsomanusNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Kamonlapat Supimon Thanich Sangsuwannukul Jatuporn Sujjitjoon Nattaporn Phanthaphol Thaweesak Chieochansin Naravat Poungvarin Sopit Wongkham Mutita Junking Pa-thai Yenchitsomanus Anti-mucin 1 chimeric antigen receptor T cells for adoptive T cell therapy of cholangiocarcinoma
description	Abstract Current treatments for cholangiocarcinoma (CCA) are largely unsuccessful due to late diagnosis at advanced stage, leading to high mortality rate. Consequently, improved therapeutic approaches are urgently needed. Chimeric antigen receptor (CAR) T cell therapy is a newly potential therapy that can recognize specific surface antigen without major histocompatibility complex (MHC) restriction. Mucin 1 (MUC1) is an attractive candidate antigen as it is highly expressed and associated with poor prognosis and survival in CCA. We, therefore, set forth to create the fourth-generation CAR (CAR4) construct containing anti-MUC1-single-chain variable fragment (scFv) and three co-stimulatory domains (CD28, CD137, and CD27) linked to CD3ζ and evaluate anti-MUC1-CAR4 T cells in CCA models. Compared to untransduced T cells, anti-MUC1-CAR4 T cells produced increased levels of TNF-α, IFN-γ and granzyme B when exposed to MUC1-expressing KKU-100 and KKU-213A CCA cells (all p < 0.05). Anti-MUC1-CAR4 T cells demonstrated specific killing activity against KKU-100 (45.88 ± 7.45%, p < 0.05) and KKU-213A cells (66.03 ± 3.14%, p < 0.001) at an effector to target ratio of 5:1, but demonstrated negligible cytolytic activity against immortal cholangiocytes. Furthermore, the anti-MUC1-CAR4 T cells could effectively disrupt KKU-213A spheroids. These activities of anti-MUC1-CAR4 T cells supports the development of this approach as an adoptive T cell therapeutic strategy for CCA.
format	article
author	Kamonlapat Supimon Thanich Sangsuwannukul Jatuporn Sujjitjoon Nattaporn Phanthaphol Thaweesak Chieochansin Naravat Poungvarin Sopit Wongkham Mutita Junking Pa-thai Yenchitsomanus
author_facet	Kamonlapat Supimon Thanich Sangsuwannukul Jatuporn Sujjitjoon Nattaporn Phanthaphol Thaweesak Chieochansin Naravat Poungvarin Sopit Wongkham Mutita Junking Pa-thai Yenchitsomanus
author_sort	Kamonlapat Supimon
title	Anti-mucin 1 chimeric antigen receptor T cells for adoptive T cell therapy of cholangiocarcinoma
title_short	Anti-mucin 1 chimeric antigen receptor T cells for adoptive T cell therapy of cholangiocarcinoma
title_full	Anti-mucin 1 chimeric antigen receptor T cells for adoptive T cell therapy of cholangiocarcinoma
title_fullStr	Anti-mucin 1 chimeric antigen receptor T cells for adoptive T cell therapy of cholangiocarcinoma
title_full_unstemmed	Anti-mucin 1 chimeric antigen receptor T cells for adoptive T cell therapy of cholangiocarcinoma
title_sort	anti-mucin 1 chimeric antigen receptor t cells for adoptive t cell therapy of cholangiocarcinoma
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/5f4b108e3f6744c6a27402aa818b2f21
work_keys_str_mv	AT kamonlapatsupimon antimucin1chimericantigenreceptortcellsforadoptivetcelltherapyofcholangiocarcinoma AT thanichsangsuwannukul antimucin1chimericantigenreceptortcellsforadoptivetcelltherapyofcholangiocarcinoma AT jatupornsujjitjoon antimucin1chimericantigenreceptortcellsforadoptivetcelltherapyofcholangiocarcinoma AT nattapornphanthaphol antimucin1chimericantigenreceptortcellsforadoptivetcelltherapyofcholangiocarcinoma AT thaweesakchieochansin antimucin1chimericantigenreceptortcellsforadoptivetcelltherapyofcholangiocarcinoma AT naravatpoungvarin antimucin1chimericantigenreceptortcellsforadoptivetcelltherapyofcholangiocarcinoma AT sopitwongkham antimucin1chimericantigenreceptortcellsforadoptivetcelltherapyofcholangiocarcinoma AT mutitajunking antimucin1chimericantigenreceptortcellsforadoptivetcelltherapyofcholangiocarcinoma AT pathaiyenchitsomanus antimucin1chimericantigenreceptortcellsforadoptivetcelltherapyofcholangiocarcinoma
_version_	1718395702487285760

Anti-mucin 1 chimeric antigen receptor T cells for adoptive T cell therapy of cholangiocarcinoma

Ejemplares similares