TCR signal strength defines distinct mechanisms of T cell dysfunction and cancer evasion.
TCR signal strength defines distinct mechanisms of T cell dysfunction and cancer evasion.
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DOI：
10.1084/jem.20201966
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发表时间：
2022-02-07
期刊：
影响因子：
--
通讯作者：
Schietinger A
中科院分区：
文献类型：
--
作者：
Shakiba M;Zumbo P;Espinosa-Carrasco G;Menocal L;Dündar F;Carson SE;Bruno EM;Sanchez-Rivera FJ;Lowe SW;Camara S;Koche RP;Reuter VP;Socci ND;Whitlock B;Tamzalit F;Huse M;Hellmann MD;Wells DK;Defranoux NA;Betel D;Philip M;Schietinger A
TCR信号强度决定了肿瘤中T细胞的分化和功能，高信号强度相互作用导致功能障碍，低信号强度相互作用导致功能惰性。将TCR信号强度微调到一个中等范围可以提高体内抗肿瘤活性。T细胞受体（TCR）信号强度是T细胞反应的关键决定因素。我们开发了一种癌症小鼠模型，在该模型中，肿瘤特异性CD8 T细胞（TST细胞）遇到具有不同TCR信号强度的肿瘤抗原。高信号强度的相互作用导致TST细胞上调抑制受体（IRs），失去效应功能，并建立功能障碍相关的分子程序。经历低信号强度相互作用的TST细胞也上调了IRs，包括PD1，但保留了细胞固有的功能状态。令人惊讶的是，无论是高信号强度还是低信号强度的相互作用都无法在体内控制肿瘤，这揭示了PD1hi TST细胞允许肿瘤逃逸的两种不同机制；高信号强度导致功能障碍，低信号强度导致功能惰性，即信号强度过低，无法介导功能性TST细胞有效杀伤癌细胞。crispr - cas9介导的信号强度微调到中间范围，提高了体内抗肿瘤活性。我们的研究确定了TCR信号强度在TST细胞功能中的作用，对基于T细胞的癌症免疫治疗具有重要意义。
TCR signal strength determines T cell differentiation and function in tumors, with high-signal-strength interactions resulting in dysfunction and low-signal-strength interactions resulting in functional inertness. Fine-tuning TCR signal strength to an intermediate range improves anti-tumor activity in vivo. T cell receptor (TCR) signal strength is a key determinant of T cell responses. We developed a cancer mouse model in which tumor-specific CD8 T cells (TST cells) encounter tumor antigens with varying TCR signal strength. High-signal-strength interactions caused TST cells to up-regulate inhibitory receptors (IRs), lose effector function, and establish a dysfunction-associated molecular program. TST cells undergoing low-signal-strength interactions also up-regulated IRs, including PD1, but retained a cell-intrinsic functional state. Surprisingly, neither high- nor low-signal-strength interactions led to tumor control in vivo, revealing two distinct mechanisms by which PD1hi TST cells permit tumor escape; high signal strength drives dysfunction, while low signal strength results in functional inertness, where the signal strength is too low to mediate effective cancer cell killing by functional TST cells. CRISPR-Cas9–mediated fine-tuning of signal strength to an intermediate range improved anti-tumor activity in vivo. Our study defines the role of TCR signal strength in TST cell function, with important implications for T cell–based cancer immunotherapies.
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影响因子：
82.9
作者：
Gros A;Parkhurst MR;Tran E;Pasetto A;Robbins PF;Ilyas S;Prickett TD;Gartner JJ;Crystal JS;Roberts IM;Trebska-McGowan K;Wunderlich JR;Yang JC;Rosenberg SA
通讯作者：
Rosenberg SA
影响因子：
46.9
作者：
Doench JG;Fusi N;Sullender M;Hegde M;Vaimberg EW;Donovan KF;Smith I;Tothova Z;Wilen C;Orchard R;Virgin HW;Listgarten J;Root DE
通讯作者：
Root DE
影响因子：
7.2
作者：
Bos R;Marquardt KL;Cheung J;Sherman LA
通讯作者：
Sherman LA
影响因子：
64.8
作者：
Daniels, Mark A.;Teixeiro, Emma;Palmer, Ed
通讯作者：
Palmer, Ed
影响因子：
7
作者：
Blankenstein T;Leisegang M;Uckert W;Schreiber H
通讯作者：
Schreiber H