Next-generation CAR T cells targeting integrin αvβ6 and PD-L1 to enhance immunotherapy for cholangiocarcinoma
Issued Date
2025-12-01
Resource Type
ISSN
07533322
eISSN
19506007
Scopus ID
2-s2.0-105022813263
Pubmed ID
41270473
Journal Title
Biomedicine and Pharmacotherapy
Volume
193
Rights Holder(s)
SCOPUS
Bibliographic Citation
Biomedicine and Pharmacotherapy Vol.193 (2025)
Suggested Citation
Somboonpatarakun C., Phanthaphol N., Suwanchiwasiri K., Ramwarungkura B., Yenchitsomanus P.t., Junking M. Next-generation CAR T cells targeting integrin αvβ6 and PD-L1 to enhance immunotherapy for cholangiocarcinoma. Biomedicine and Pharmacotherapy Vol.193 (2025). doi:10.1016/j.biopha.2025.118806 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/113338
Title
Next-generation CAR T cells targeting integrin αvβ6 and PD-L1 to enhance immunotherapy for cholangiocarcinoma
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Corresponding Author(s)
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Abstract
Cholangiocarcinoma (CCA) is an aggressive epithelial malignancy characterized by poor prognosis, limited treatment options, and high recurrence rates even after surgery. Chimeric antigen receptor (CAR) T cell therapy has achieved notable success in hematologic malignancies, but its efficacy in solid tumors such as CCA is hindered by the immunosuppressive tumor microenvironment, particularly through PD-1/PD-L1 axis. To address these barriers, we developed a sixth-generation CAR T cell, A20 CAR6, incorporating the A20 peptide, a high-affinity ligand for integrin αvβ6—a tumor-associated antigen frequently overexpressed in CCA. Beyond antigen targeting, A20 CAR6 T cells are engineered to secrete a bispecific protein engager (BiPE) that binds PD-L1 on tumor cells and CD3 on T cells. This dual-function design aims to neutralize PD-L1–mediated immune suppression and recruit both CAR and bystander T cells to enhance tumor killing. Compared with conventional fourth-generation A20 CAR4 T cells lacking BiPE secretion, A20 CAR6 T cells exhibited superior cytotoxicity, cytokine production, and proliferation against integrin αvβ6<sup>+</sup>/PD-L1<sup>+</sup> CCA cells. Notably, the secreted αPD-L1/αCD3 BiPE augmented CAR T cell activity and redirected non-engineered T cells to target tumor cells, amplifying the overall anti-tumor response. These findings suggest that A20 CAR6 T cells represent a promising next-generation immunotherapy with the potential to overcome key resistance mechanisms in CCA and improve treatment outcomes.