Center of Life Sciences, Skolkovo Institute of Science and Technology, Moscow, Russian Federation.
Genomics of Adaptive Immunity Department, Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russian Federation.
Elife. 2022 Apr 4;11:e77274. doi: 10.7554/eLife.77274.
Adoptive cell transfer (ACT) is a promising approach to cancer immunotherapy, but its efficiency fundamentally depends on the extent of tumor-specific T cell enrichment within the graft. This can be estimated via activation with identifiable neoantigens, tumor-associated antigens (TAAs), or living or lysed tumor cells, but these approaches remain laborious, time-consuming, and functionally limited, hampering clinical development of ACT. Here, we demonstrate that homology cluster analysis of T cell receptor (TCR) repertoires efficiently identifies tumor-reactive TCRs allowing to: (1) detect their presence within the pool of tumor-infiltrating lymphocytes (TILs); (2) optimize TIL culturing conditions, with IL-2/IL-21/anti-PD-1 combination showing increased efficiency; (3) investigate surface marker-based enrichment for tumor-targeting T cells in freshly isolated TILs (enrichment confirmed for CD4 and CD8 PD-1/CD39 subsets), or re-stimulated TILs (informs on enrichment in 4-1BB-sorted cells). We believe that this approach to the rapid assessment of tumor-specific TCR enrichment should accelerate T cell therapy development.
过继细胞转移 (ACT) 是一种很有前途的癌症免疫疗法，但它的效率从根本上取决于移植物中肿瘤特异性 T 细胞的富集程度。这可以通过与可识别的新抗原、肿瘤相关抗原 (TAA) 或活或裂解的肿瘤细胞的激活来估计，但这些方法仍然繁琐、耗时且功能有限，阻碍了 ACT 的临床发展。在这里，我们证明了 T 细胞受体 (TCR) 库的同源聚类分析能够有效地识别肿瘤反应性 TCR，从而能够：(1) 在肿瘤浸润淋巴细胞 (TIL) 池中检测其存在；(2) 优化 TIL 培养条件，IL-2/IL-21/抗 PD-1 联合显示出更高的效率；(3) 研究基于表面标志物的新鲜分离 TIL 中肿瘤靶向 T 细胞的富集（CD4 和 CD8 PD-1/CD39 亚群的富集得到证实），或再刺激 TIL（告知 4-1BB 分选细胞的富集情况）。我们相信，这种快速评估肿瘤特异性 TCR 富集的方法应该会加速 T 细胞治疗的发展。
