School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China.
Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran 1665666311, Iran.
Biomolecules. 2022 Sep 14;12(9):1296. doi: 10.3390/biom12091296.
Chimeric antigen receptor (CAR) T-cell therapy is one of the cancer treatment modalities that has recently shown promising results in treating hematopoietic malignancies. However, one of the obstacles that need to be addressed in solid tumors is the on-target and off-tumor cytotoxicity due to the lack of specific tumor antigens with low expression in healthy cells. Placental alkaline phosphatase (PLAP) is a shared placenta- and tumor-associated antigen (TAA) that is expressed in ovarian, cervical, colorectal, and prostate cancers and is negligible in normal cells. In this study, we constructed second-generation CAR T cells with a fully human scFv against PLAP antigen andthen evaluated the characteristics of PLAP CAR T cells in terms of tonic signaling and differentiation in comparison with ΔPLAP CAR T cells and CD19 CAR T cells. In addition, by co-culturing PLAP CAR T cells with HeLa and CaSki cells, we analyzed the tumor-killing functions and the secretion of anti-tumor molecules. Results showed that PLAP CAR T cells not only proliferated during co-culture with cancer cells but also eliminated them in vitro. We also observed increased secretion of IL-2, granzyme A, and IFN-γ by PLAP CAR T cells upon exposure to the target cells. In conclusion, PLAP CAR T cells are potential candidates for further investigation in cervical cancer and, potentially, other solid tumors.
嵌合抗原受体 (CAR) T 细胞疗法是最近在治疗血液恶性肿瘤方面显示出有前景的癌症治疗方法之一。然而，在实体瘤中需要解决的一个障碍是由于缺乏在健康细胞中低表达的特异性肿瘤抗原而导致的靶内和肿瘤外细胞毒性。胎盘碱性磷酸酶 (PLAP) 是一种与胎盘和肿瘤相关的共同抗原 (TAA)，在卵巢癌、宫颈癌、结直肠癌和前列腺癌中表达，在正常细胞中可忽略不计。在这项研究中，我们构建了针对 PLAP 抗原的第二代全人源 scFv 的 CAR T 细胞，然后评估了 PLAP CAR T 细胞在 tonic 信号和分化方面的特性，与 ΔPLAP CAR T 细胞和 CD19 CAR T 细胞进行了比较。此外，通过将 PLAP CAR T 细胞与 HeLa 和 CaSki 细胞共培养，我们分析了肿瘤杀伤功能和抗肿瘤分子的分泌。结果表明，PLAP CAR T 细胞不仅在与癌细胞共培养期间增殖，而且还在体外消除了它们。我们还观察到 PLAP CAR T 细胞在暴露于靶细胞时 IL-2、颗粒酶 A 和 IFN-γ 的分泌增加。总之，PLAP CAR T 细胞是进一步研究宫颈癌以及其他实体瘤的潜在候选者。
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