美国康涅狄格大学医学院Pramod K. Srivastava团队近期取得重要工作进展，他们研究提出，低亲和力T细胞驱动小鼠和人类的内源性肿瘤免疫。相关研究成果2025年1月9日在线发表于《自然—免疫学》杂志上。

据介绍，T细胞能识别癌细胞上的新表位肽-主要组织相容性复合体I类分子。T细胞受体-肽-主要组织相容性复合体I类分子相互作用的强度（或亲和力）是癌症免疫控制中的一个关键变量。

研究人员分析了具有不同亲和力的新表位特异性CD8细胞，并发现低亲和力T细胞是小鼠体内癌症控制的唯一介导因素，且在小鼠和人类中，也只有低亲和力T细胞对免疫检查点阻断疗法有反应。高亲和力T细胞不仅无效，还具有免疫抑制作用。造成这些差异的机制基础在于高亲和力细胞具有更高的耗竭状态。高亲和力T细胞有着独特的转录组图谱，研究人员利用该图谱计算出了一个 “亲和力分数”，随后借助这个分数通过计算机模拟在小鼠和人类中鉴别出低亲和力和高亲和力的T细胞。研究发现，有着相同T细胞受体的CD8⁺ T细胞在亲和力方面表现出很大差异，这表明T细胞活性还存在另外一层调控机制。

总之，这一研究除了能让人们更好地理解内源性T细胞对癌症的应答外，或许还能为未来的免疫治疗策略提供指导。

附：英文原文

Title: Low-avidity T cells drive endogenous tumor immunity in mice and humans

Author: Singhaviranon, Summit, Dempsey, Joseph P., Hagymasi, Adam T., Mandoiu, Ion I., Srivastava, Pramod K.

Issue&Volume: 2025-01-09

Abstract: T cells recognize neoepitope peptide-major histocompatibility complex class I on cancer cells. The strength (or avidity) of the T cell receptor–peptide-major histocompatibility complex class I interaction is a critical variable in immune control of cancers. Here, we analyze neoepitope-specific CD8 cells of distinct avidities and show that low-avidity T cells are the sole mediators of cancer control in mice and are solely responsive to checkpoint blockade in mice and humans. High-avidity T cells are ineffective and immune-suppressive. The mechanistic basis of these differences lies in the higher exhaustion status of high-avidity cells. High-avidity T cells have a distinct transcriptomic profile that is used here to calculate an ‘avidity score’, which we then use for in silico identification of low-avidity and high-avidity T cells in mice and humans. Surprisingly, CD8+ T cells with identical T cell receptors exhibit wide variation in avidities, suggesting an additional level of regulation of T cell activity. Aside from providing a better understanding of endogenous T cell responses to cancer, these findings might instruct future immunotherapy strategies.

DOI: 10.1038/s41590-024-02044-z

Source: https://www.nature.com/articles/s41590-024-02044-z