Adaptimmune Ltd., Milton Park, Abingdon, United Kingdom;
Adaptimmune Ltd., Milton Park, Abingdon, United Kingdom.
J Immunol. 2022 Jan 1;208(1):169-180. doi: 10.4049/jimmunol.2001357. Epub 2021 Dec 1.
Adoptive T cell therapy with T cells expressing affinity-enhanced TCRs has shown promising results in phase 1/2 clinical trials for solid and hematological tumors. However, depth and durability of responses to adoptive T cell therapy can suffer from an inhibitory tumor microenvironment. A common immune-suppressive agent is TGF-β, which is secreted by tumor cells and cells recruited to the tumor. We investigated whether human T cells could be engineered to be resistant to inhibition by TGF-β. Truncating the intracellular signaling domain from TGF-β receptor (TGFβR) II produces a dominant-negative receptor (dnTGFβRII) that dimerizes with endogenous TGFβRI to form a receptor that can bind TGF-β but cannot signal. We previously generated specific peptide enhanced affinity receptor TCRs recognizing the HLA-A*02-restricted peptides New York esophageal squamous cell carcinoma 1 (NY-ESO-1)/l-Ag family member-1A (TCR: GSK3377794, formerly NY-ESO-1) and melanoma Ag gene A10 (TCR: ADP-A2M10, formerly melanoma Ag gene A10). In this article, we show that exogenous TGF-β inhibited in vitro proliferation and effector functions of human T cells expressing these first-generation high-affinity TCRs, whereas inhibition was reduced or abolished in the case of second-generation TCRs coexpressed with dnTGFβRII (e.g., GSK3845097). TGF-β isoforms and a panel of TGF-β-associated genes are overexpressed in a range of cancer indications in which NY-ESO-1 is commonly expressed, particularly in synovial sarcoma. As an example, immunohistochemistry/RNAscope identified TGF-β-positive cells close to T cells in tumor nests and stroma, which had low frequencies of cells expressing IFN-γ in a non-small cell lung cancer setting. Coexpression of dnTGFβRII may therefore improve the efficacy of TCR-transduced T cells.
过继性 T 细胞疗法中，表达亲和力增强 TCR 的 T 细胞在实体瘤和血液系统肿瘤的 1/2 期临床试验中显示出良好的效果。然而，过继性 T 细胞疗法的深度和持久性可能会受到抑制性肿瘤微环境的影响。一种常见的免疫抑制药物是 TGF-β，它由肿瘤细胞和募集到肿瘤中的细胞分泌。我们研究了人类 T 细胞是否可以被设计成对 TGF-β的抑制具有抗性。截断 TGF-β 受体（TGFβR）II 的细胞内信号结构域会产生一种显性负受体（dnTGFβRII），它与内源性 TGFβRI 二聚化，形成一种可以结合 TGF-β但不能发出信号的受体。我们之前生成了特异性肽增强亲和力受体 TCR，识别 HLA-A*02 限制性肽 NY-ESO-1/l-Ag 家族成员-1A（TCR：GSK3377794，前 NY-ESO-1）和黑色素瘤 Ag 基因 A10（TCR：ADP-A2M10，前黑色素瘤 Ag 基因 A10）。在本文中，我们表明，外源性 TGF-β抑制表达这些第一代高亲和力 TCR 的人 T 细胞的体外增殖和效应功能，而在共表达 dnTGFβRII 的情况下，抑制作用降低或消除（例如，GSK3845097）。TGF-β 同工型和一组 TGF-β 相关基因在 NY-ESO-1 普遍表达的多种癌症适应症中过度表达，特别是在滑膜肉瘤中。例如，免疫组化/RNAscope 在肿瘤巢和基质中鉴定出 TGF-β 阳性细胞靠近 T 细胞，这些细胞在非小细胞肺癌环境中 IFN-γ 表达细胞的频率较低。共表达 dnTGFβRII 可能因此会提高 TCR 转导的 T 细胞的疗效。
