Enhancing T cell cytotoxicity against lung cancer with an αPD-L1 protein engager and gemcitabine combination therapy
Issued Date
2025-07-01
Resource Type
ISSN
07533322
eISSN
19506007
Scopus ID
2-s2.0-105005165818
Journal Title
Biomedicine and Pharmacotherapy
Volume
188
Rights Holder(s)
SCOPUS
Bibliographic Citation
Biomedicine and Pharmacotherapy Vol.188 (2025)
Suggested Citation
Thepmalee C., Sawasdee N., Thongyim S., Poungvarin N., Yenchitsomanus P.t., Panya A. Enhancing T cell cytotoxicity against lung cancer with an αPD-L1 protein engager and gemcitabine combination therapy. Biomedicine and Pharmacotherapy Vol.188 (2025). doi:10.1016/j.biopha.2025.118161 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/110327
Title
Enhancing T cell cytotoxicity against lung cancer with an αPD-L1 protein engager and gemcitabine combination therapy
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Corresponding Author(s)
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Abstract
The overexpression of programmed cell death ligand 1 (PD-L1), a critical immune checkpoint protein, is associated with poor prognosis and reduced survival in lung cancer patients. Monoclonal antibodies targeting the PD-1/PD-L1 axis have been approved to disrupt this interaction and prevent immune cell exhaustion. Herein, to enhance the efficacy of PD-1/PD-L1 blockade, we investigated a bispecific αPD-L1 × αCD3 protein engager (αPD-L1 × αCD3 BIPE). The αPD-L1 × αCD3 BIPE consists of an anti-CD3 single-chain variable fragment (scFv) linked to an anti-PD-L1 scFv, allowing it to bind to CD3-positive T cells simultaneously and PD-L1-overexpressing cancer cells. In co-culture assays with T cells and non-small cell lung cancer (NSCLC) cell lines—A549, NCI-H460, and NCI-H1975—treatment with the BIPE significantly enhanced T-cell-mediated cytotoxicity. The killing efficiency correlated with PD-L1 expression levels, with the highest cytotoxic activity observed in NCI-H1975 (high PD-L1 expression), followed by NCI-H460 (moderate PD-L1 expression) and A549 (low PD-L1 expression). Furthermore, combining the BIPE with the standard chemotherapeutic agent gemcitabine further improved anti-tumor activity. This effect was likely due to gemcitabine-induced upregulation of PD-L1 and MHC class I expression on cancer cells, enhancing T-cell recognition and cytotoxicity. These findings suggest that combining αPD-L1 × αCD3 BIPE with gemcitabine is promising for enhancing immune checkpoint blockade and augmenting anti-tumor immunity in NSCLC.