CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：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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T细胞受体（TCR）信号强度是T细胞应答的关键决定因素。我们建立了一种癌症小鼠模型，其中肿瘤特异性CD8 T细胞（TST细胞）以不同TCR信号强度 encounter 肿瘤抗原。高信号强度相互作用导致TST细胞上调抑制性受体（IRs），丧失效应功能，并建立功能障碍相关分子程序。经历低信号强度相互作用的TST细胞也上调IRs，包括PD1，但保留细胞内在功能状态。出乎意料的是，高信号强度和低信号强度相互作用均未导致体内肿瘤控制，揭示了PD1hi TST细胞允许肿瘤逃逸的两种不同机制；高信号强度驱动功能障碍，而低信号强度导致功能性惰性，其中信号强度太低，无法由功能性TST细胞介导有效的癌细胞杀伤。CRISPR-Cas9介导的信号强度精细调节至中间范围改善了体内抗肿瘤活性。我们的研究定义了TCR信号强度在TST细胞功能中的作用，对基于T细胞的癌症免疫疗法具有重要意义。
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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