Combination gemcitabine and PD-L1xCD3 bispecific T cell engager (BiTE) enhances T lymphocyte cytotoxicity against cholangiocarcinoma cells

Wathikthinnakon, Methi and Luangwattananun, Piriya and Sawasdee, Nunghathai and Chiawpanit, Chutipa and Lee, Vannajan Sanghiran and Nimmanpipug, Piyarat and Tragoolpua, Yingmanee and Rotarayanont, Siriphorn and Sangsuwannukul, Thanich and Phanthaphol, Nattaporn and Wutti-in, Yupanun and Somboonpatarakun, Chalermchai and Chieochansin, Thaweesak and Junking, Mutita and Sujjitjoon, Jatuporn and Yenchitsomanus, Pa-thai and Panya, Aussara (2022) Combination gemcitabine and PD-L1xCD3 bispecific T cell engager (BiTE) enhances T lymphocyte cytotoxicity against cholangiocarcinoma cells. Scientific Reports, 12 (1). ISSN 2045-2322, DOI

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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.

Item Type: Article
Funders: Program Management Unit-Competitiveness (PMUC) grant (C10F630063/2020), Siriraj Research Fund, Faculty of Medicine Siriraj Hospital, Mahidol University (R016034008), Research Center in Bioresources for Agriculture, Industry and Medicine, Faculty of Science, Chiang Mai University
Uncontrolled Keywords: Combination; Gemcitabine; PD-L1xCD3 bispecific T cell engager; (BiTE); T lymphocyte cytotoxicity; Cholangiocarcinoma cells
Subjects: Q Science > Q Science (General)
Q Science > QD Chemistry
Divisions: Faculty of Science > Department of Chemistry
Depositing User: Ms. Juhaida Abd Rahim
Date Deposited: 15 Sep 2023 08:35
Last Modified: 15 Sep 2023 08:35

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