Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, F-25000, Besançon, France.
University Hospital of Besançon, Department of Medical Oncology, F-25000, Besançon, France.
Cancer Gene Ther. 2022 Jul;29(7):961-972. doi: 10.1038/s41417-021-00395-5. Epub 2021 Oct 13.
Engineered T-cell therapies have proven to be successful in cancer and their clinical effectiveness is directly correlated with the infused T-cell differentiation profile. Indeed, stem cell memory and central memory T cells proliferate and persist longer in vivo compared with more-differentiated T cells, while conferring enhanced antitumor activity. Here, we propose an optimized process using cord blood (CB) to generate minimally differentiated T-cell products in terms of phenotype, function, gene expression, and metabolism, using peripheral blood (PB)-derived T cells cultured with IL-2 as a standard. Phenotypically, CB-derived T cells, particularly CD4 T cells, are less differentiated than their PB counterparts when cultured with IL-2 or with IL-7 and IL-15. Furthermore, culture with IL-7 and IL-15 enables better preservation of less-differentiated CB-derived T cells compared with IL-2. In addition, transcriptomic and metabolic assessments of CB-derived transgenic T cells cultured with IL-7 and IL-15 point out their naivety and stemness signature. These relatively quiescent transgenic T cells are nevertheless primed for secondary stimulation and cytokine production. In conclusion, our study indicates that CB may be used as a source of early differentiated T cells to develop more effective adoptive cancer immunotherapy.
工程化 T 细胞疗法已被证明在癌症治疗中非常有效，其临床疗效与输注的 T 细胞分化谱直接相关。事实上，与更分化的 T 细胞相比，干细胞记忆和中央记忆 T 细胞在体内增殖和持续时间更长，同时赋予更强的抗肿瘤活性。在这里，我们提出了一种使用脐带血 (CB) 的优化工艺，使用外周血 (PB) 来源的 T 细胞在 IL-2 培养的基础上，生成表型、功能、基因表达和代谢方面最小分化的 T 细胞产品。表型上，与 PB 来源的 T 细胞相比，用 IL-2 或 IL-7 和 IL-15 培养的 CB 来源的 T 细胞，特别是 CD4 T 细胞，分化程度较低。此外，与 IL-2 相比，用 IL-7 和 IL-15 培养可更好地保存分化程度较低的 CB 来源的 T 细胞。此外，对用 IL-7 和 IL-15 培养的 CB 来源的转基因 T 细胞进行转录组和代谢评估，指出其幼稚和干性特征。这些相对静止的转基因 T 细胞仍然可以被再次刺激并产生细胞因子。总之，我们的研究表明，CB 可作为早期分化 T 细胞的来源，以开发更有效的过继性癌症免疫疗法。
