Wang Shuo, Shi Qi, Zhao Yuze, Song Yuguang, Qiao Guoliang, Liu Guangjie, Zhu Qian, Huang Lefu, Xu Chang, Liu Bing, Chen Zheng, Huang Hongyan
Department of Medical Oncology, Beijing Key Laboratory for Therapeutic Cancer Vaccines, Capital Medical University Cancer Center, Beijing Shijitan Hospital, Capital Medical University Beijing 100038, China.
Department of Surgical Oncology, Massachusetts General Hospital 55, Fruit Street, Boston 02114, MA, USA.
Am J Cancer Res. 2022 May 15;12(5):2203-2215. eCollection 2022.
The adoptive cell therapy (ACT) and delivery of ex vivo activated cellular products, such as dendritic cells (DCs), NK cells, and T cells, have shown promise for the treatment of gastric cancer (GC). However, it is unknown which cells can improve patient survival. This study was focused on the antitumour activity of a subset of these cellular products and their relationships with clinical outcomes. Nineteen patients were enrolled at the Capital Medical University Cancer Center, Beijing Shijitan Hospital, from June 1, 2013, to May 30, 2016. CD8PD1 T-cell sorting was carried out using flow cytometry, and the T-cell receptor (TCR) repertoire during ex vivo expansion for 15 days was analyzed by next-generation sequencing. After 15 days of culture, the number of CD8 T cells had increased significantly, and the number of CD4 T cells had increased correspondingly. After ex vivo expansion, CD8 T cells exhibited significantly enhanced expression of PD-1, LAG-3, and TIM-3 but not 4-1BB. Survival analysis showed that patients with a pro/pre value of CD8PD-1 T cells >2.4 had significantly favorable overall survival (OS) (median OS time, 248 days versus 96 days, P=0.02) and progression-free survival (PFS) (median PFS time, 183 days vs. 77 days, P=0.002). The sorted CD8PD-1 T cells displayed enhanced antitumor activity and increased IFN-γ secretion after coculture with autologous tumor cell lines. TCR repertoire diversity was decreased after ex vivo expansion, which decreased the Shannon index and increased the clonality value. The prognosis of patients was significantly improved and was associated with the extent of CD8PD-1 T-cell expansion. In summary, this study showed that after ex vivo expansion for 15 days, CD8PD-1 T cells could be identified as tumor-reactive cells in patients treated for GC. Changing TCR species can predict the extent of CD3CD8PD1 T-cell growth and the effect of ACT treatment.
过继性细胞疗法（ACT）以及离体激活细胞产物（如树突状细胞（DC）、自然杀伤细胞（NK）和T细胞）的递送已显示出治疗胃癌（GC）的潜力。然而，尚不清楚哪种细胞能提高患者生存率。本研究聚焦于这些细胞产物亚群的抗肿瘤活性及其与临床结局的关系。2013年6月1日至2016年5月30日，19例患者在北京世纪坛医院首都医科大学癌症中心入组。使用流式细胞术进行CD8⁺PD-1⁺ T细胞分选，并通过下一代测序分析体外扩增15天期间的T细胞受体（TCR）库。培养15天后，CD8⁺ T细胞数量显著增加，CD4⁺ T细胞数量相应增加。体外扩增后，CD8⁺ T细胞表现出PD-1、LAG-3和TIM-3表达显著增强，但4-1BB未增强。生存分析表明，CD8⁺PD-1⁺ T细胞的前体/预激活值>2.4的患者总生存期（OS）显著更好（中位OS时间，248天对96天，P = 0.02）和无进展生存期（PFS）显著更好（中位PFS时间，183天对77天，P = 0.002）。分选的CD8⁺PD-1⁺ T细胞与自体肿瘤细胞系共培养后显示出增强的抗肿瘤活性和增加的IFN-γ分泌。体外扩增后TCR库多样性降低，香农指数降低，克隆性值增加。患者的预后显著改善，且与CD8⁺PD-1⁺ T细胞扩增程度相关。总之，本研究表明，体外扩增15天后，CD8⁺PD-1⁺ T细胞可被鉴定为接受GC治疗患者中的肿瘤反应性细胞。改变TCR种类可预测CD3⁺CD8⁺PD-1⁺ T细胞生长程度和ACT治疗效果。
