Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.
Nat Rev Immunol. 2021 Dec;21(12):769-784. doi: 10.1038/s41577-021-00539-6. Epub 2021 Apr 20.
The antitumour activity of endogenous or adoptively transferred tumour-specific T cells is highly dependent on their differentiation status. It is now apparent that less differentiated T cells compared with fully differentiated effector T cells have better antitumour therapeutic effects owing to their enhanced capacity to expand and their long-term persistence. In patients with cancer, the presence of endogenous or adoptively transferred T cells with stem-like memory or precursor phenotype correlates with improved therapeutic outcomes. Advances in our understanding of T cell differentiation states at the epigenetic and transcriptional levels have led to the development of novel methods to generate tumour-specific T cells - namely, chimeric antigen receptor T cells - that are more persistent and resistant to the development of dysfunction. These include the use of novel culture methods before infusion, modulation of transcriptional, metabolic and/or epigenetic programming, and strategies that fine-tune antigen receptor signalling. This Review discusses existing barriers and strategies to overcome them for successful T cell expansion and persistence in the context of adoptive T cell immunotherapy for solid cancers.
内源性或过继转移的肿瘤特异性 T 细胞的抗肿瘤活性高度依赖于其分化状态。现在很明显，与完全分化的效应 T 细胞相比，分化程度较低的 T 细胞具有更好的抗肿瘤治疗效果，因为它们具有更强的扩增能力和长期持久性。在癌症患者中，内源性或过继转移的具有干细胞样记忆或前体表型的 T 细胞的存在与改善的治疗结果相关。我们对 T 细胞分化状态在表观遗传和转录水平的理解的进展，导致了产生肿瘤特异性 T 细胞（即嵌合抗原受体 T 细胞）的新方法的发展，这些方法具有更好的持久性和对功能障碍发展的抗性。其中包括在输注前使用新的培养方法、调节转录、代谢和/或表观遗传编程以及微调抗原受体信号的策略。本综述讨论了在实体瘤过继性 T 细胞免疫治疗中，为成功扩增和维持 T 细胞而克服现有障碍和策略的相关内容。
