Sawasdee Nunghathai, Thepmalee Chutamas, Junking Mutita, Okada Seiji, Panya Aussara, Yenchitsomanus Pa-Thai
Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand; Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand.
Division of Biochemistry, School of Medical Sciences, University of Phayao, Mueang Phayao 56000, Thailand.
Biomed Pharmacother. 2025 Mar;184:117878. doi: 10.1016/j.biopha.2025.117878. Epub 2025 Jan 31.
Multiple myeloma (MM) is an incurable plasma cell malignancy characterized by frequent relapse due to acquired treatment resistance, underscoring the need for innovative therapies, particularly for relapsed cases. This study explores the effects of low-dose bortezomib (BTZ) on programmed death ligand 1 (PD-L1) expression in MM cell lines and its potential to enhance T cell-mediated anti-tumor responses. Utilizing this PD-L1 upregulation, we employed bispecific αPD-L1 × αCD3 T cell engager-armed T cells (BATs) to block PD-L1 signaling and activate T cells. Flow cytometry confirmed that BATs selectively bound CD3 on T cells and PD-L1 on cancer cells, inducing T cell activation and proliferation without directly affecting cancer cell viability. BATs' cytotoxic activity was evaluated in MM cell lines with or without BTZ-induced PD-L1 expression. While KMS-12-PE cells showed no significant response, BATs significantly increased cell death in L363 cells, with further enhancement by BTZ. In RPMI-8226 cells, BATs demonstrated robust cytotoxicity, further amplified by BTZ. These results suggest that BATs, particularly in combination with BTZ, represent a promising strategy for treating MM, including bortezomib-resistant cases.
多发性骨髓瘤（MM）是一种无法治愈的浆细胞恶性肿瘤，其特征是由于获得性治疗耐药而频繁复发，这突出了对创新疗法的需求，特别是对于复发病例。本研究探讨了低剂量硼替佐米（BTZ）对MM细胞系中程序性死亡配体1（PD-L1）表达的影响及其增强T细胞介导的抗肿瘤反应的潜力。利用这种PD-L1上调，我们采用双特异性αPD-L1×αCD3 T细胞衔接器武装的T细胞（BATs）来阻断PD-L1信号传导并激活T细胞。流式细胞术证实，BATs选择性地结合T细胞上的CD3和癌细胞上的PD-L1，诱导T细胞活化和增殖，而不直接影响癌细胞的活力。在有或没有BTZ诱导的PD-L1表达的MM细胞系中评估了BATs的细胞毒性活性。虽然KMS-12-PE细胞没有显示出明显的反应，但BATs显著增加了L363细胞中的细胞死亡，BTZ进一步增强了这种作用。在RPMI-8226细胞中，BATs表现出强大的细胞毒性，BTZ进一步放大了这种毒性。这些结果表明，BATs，特别是与BTZ联合使用时，代表了一种治疗MM的有前景的策略，包括硼替佐米耐药病例。
