Department of Haematology, Cancer Institute, University College London, London, United Kingdom. Institute of Immunity and Transplantation, University College London, London, United Kingdom.
Institute of Immunity and Transplantation, University College London, London, United Kingdom.
Cancer Res. 2015 Jul 1;75(13):2641-52. doi: 10.1158/0008-5472.CAN-14-3283. Epub 2015 Apr 22.
A key challenge in the field of T-cell immunotherapy for cancer is creating a suitable platform for promoting differentiation of effector cells while at the same time enabling self-renewal needed for long-term memory. Although transfer of less differentiated memory T cells increases efficacy through greater expansion and persistence in vivo, the capacity of such cells to sustain effector functions within immunosuppressive tumor microenvironments may still be limiting. We have therefore directly compared the impact of effector versus memory differentiation of therapeutic T cells in tumor-bearing mice by introducing molecular switches that regulate cell fate decisions via mTOR. Ectopic expression of RAS homolog enriched in brain (RHEB) increased mTORC1 signaling, promoted a switch to aerobic glycolysis, and increased expansion of effector T cells. By rapidly infiltrating tumors, RHEB-transduced T cells significantly reduced the emergence of immunoedited escape variants. In contrast, expression of proline-rich Akt substrate of 40 kDa (PRAS40) inhibited mTORC1, promoted quiescence, and blocked tumor infiltration. Fate mapping studies following transient expression of PRAS40 demonstrated that mTORC1(low) T cells made no contribution to initial tumor control but instead survived to become memory cells proficient in generating recall immunity. Our data support the design of translational strategies for generating heterogeneous T-cell immunity against cancer, with the appropriate balance between promoting effector differentiation and self-renewal. Unlike pharmacologic inhibitors, the genetic approach described here allows for upregulation as well as inhibition of the mTORC1 pathway and is highly selective for the therapeutic T cells without affecting systemic mTORC1 functions.
在癌症的 T 细胞免疫治疗领域，一个关键的挑战是创建一个合适的平台，既能促进效应细胞的分化，又能使自我更新，从而产生长期记忆。虽然转移分化程度较低的记忆 T 细胞可以通过更大程度的扩增和体内持续存在来提高疗效，但这些细胞在免疫抑制性肿瘤微环境中维持效应功能的能力可能仍然有限。因此，我们通过引入通过 mTOR 调节细胞命运决定的分子开关，直接比较了治疗性 T 细胞在荷瘤小鼠中效应细胞与记忆细胞分化的影响。脑丰富的 RAS 同源物（RHEB）的异位表达增加了 mTORC1 信号，促进了有氧糖酵解的转变，并增加了效应 T 细胞的扩增。通过快速浸润肿瘤，RHEB 转导的 T 细胞显著减少了免疫编辑逃逸变体的出现。相比之下，富含脯氨酸的 Akt 底物 40 kDa（PRAS40）的表达抑制了 mTORC1，促进了静止，并阻止了肿瘤浸润。PRAS40 短暂表达后的命运图谱研究表明，mTORC1（低）T 细胞对初始肿瘤控制没有贡献，但存活下来成为记忆细胞，能够有效地产生回忆免疫。我们的数据支持设计针对癌症的异质性 T 细胞免疫的转化策略，在促进效应细胞分化和自我更新之间取得适当的平衡。与药理抑制剂不同，这里描述的遗传方法允许上调和抑制 mTORC1 途径，并且对治疗性 T 细胞具有高度选择性，而不影响系统的 mTORC1 功能。
