肿瘤细胞治疗研究
英文原题：CAR-T cells based on a TCR mimic nanobody targeting HPV16 E6 exhibit antitumor activity against cervical cancer.
这些结果表明，HPV-16+ 宫颈癌可被基于 F5 纳米抗体的 CAR-T 细胞靶向，为治疗 HPV-16+ 恶性肿瘤提供了一种有价值的替代策略。
人乳头瘤病毒（HPV）E6和E7癌蛋白被认为是HPV相关癌症有前景的靶点。本研究采用嵌合抗原受体（CAR）形式，评估新型T细胞受体模拟（TCRm）纳米抗体靶向与人类白细胞抗原（HLA）-A*02:01结合的E6 29-38肽复合物的能力。我们通过噬菌体展示筛选分离出两种单峰骆驼纳米抗体F5和G9。与G9相比，F5能够更有效地结合细胞表达的复合物，包括肽脉冲处理的T2细胞、过表达293E6细胞，以及宫颈癌细胞系CaSki和SS4050。基于F5纳米抗体构建的CAR-T细胞可通过激活活化T细胞核因子（NFAT）和核因子κB（NF-κB）信号通路，在体外特异性杀伤包括293E6、CaSki和SS4050在内的靶细胞。重要的是，F5 CAR-T细胞可抑制小鼠CaSki和SS4050肿瘤异种移植瘤生长。这些发现表明，HPV-16阳性宫颈癌可由基于F5纳米抗体的CAR-T细胞靶向，为治疗HPV-16阳性恶性肿瘤提供了一种有价值的替代策略。
The E6 and E7 oncoproteins of human papillomavirus (HPV) are considered promising targets for HPV-related cancers. In this study, we evaluated novel T cell receptor mimic (TCRm) nanobodies targeting the E6 29-38 peptide complexed with human leukocyte antigen (HLA)-A 02:01 in the chimeric antigen receptor (CAR) format. We isolated two dromedary camel nanobodies, F5 and G9, through phage display screening. F5 bound more efficiently to the complex expressed on cells, including peptide-pulsed T2, overexpressed 293E6, and cervical cancer lines CaSki and SS4050, compared to G9. CAR-T cells based on the F5 nanobody specifically killed target cells, including 293E6, CaSki, and SS4050 in vitro , through activation of nuclear factor of activated T cells (NFAT) and nuclear factor B (NF- B) signaling. Importantly, F5 CAR-T cells inhibited the growth of CaSki and SS4050 tumor xenografts in mice. These findings demonstrate that HPV-16+ cervical cancer can be targeted by F5 nanobody-based CAR-T cells, offering a valuable alternative strategy for treating HPV-16+ malignancies.
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