Phenotype, specificity and avidity of antitumour CD8(+) T cells in melanoma.
Phenotype, specificity and avidity of antitumour CD8(+) T cells in melanoma.
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DOI：
10.1038/s41586-021-03704-y
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发表时间：
2021-08
期刊：
影响因子：
64.8
通讯作者：
中科院分区：
文献类型：
--
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T细胞受体（TCR）和它们的同源肿瘤抗原之间的相互作用是抗肿瘤免疫应答的核心;然而，表型特征和TCR特性之间的关系尚未得到很好的阐明。在这里，我们表明，通过连接TCR的抗原特异性和黑色素瘤浸润淋巴细胞在单细胞分辨率的细胞表型，肿瘤特异性形状的表达状态的肿瘤内CD 8 + T细胞。非肿瘤反应性T细胞富含病毒特异性，并表现出非耗尽记忆表型，而黑色素瘤反应性淋巴细胞主要表现出耗尽状态，包括不同的分化水平，但很少获得记忆特性。这些耗尽的表型在对公共过表达的黑素瘤抗原（在不同肿瘤中共有）或个人新抗原（对每种肿瘤特异性）特异性的克隆型中均观察到。这种肿瘤抗原的识别由TCR提供，其亲和力与黑素瘤细胞中同源靶标的丰度呈负相关，并与肽-人白细胞抗原（HLA）复合物的结合亲和力成比例。外周血中TCR克隆型的持久性受到肿瘤内耗竭水平的负面影响，并且在对免疫检查点阻断反应不良的患者中增加，这与残留肿瘤抗原介导的慢性刺激一致。通过揭示肿瘤抗原的质量和数量如何驱动肿瘤微环境中T细胞反应的特征，我们深入了解了抗黑色素瘤TCR库的特性。
Interactions between T cell receptors (TCRs) and their cognate tumour antigens are central to antitumour immune responses; however, the relationship between phenotypic characteristics and TCR properties is not well elucidated. Here we show, by linking the antigenic specificity of TCRs and the cellular phenotype of melanoma-infiltrating lymphocytes at single-cell resolution, that tumour specificity shapes the expression state of intratumoural CD8+ T cells. Non-tumour-reactive T cells were enriched for viral specificities and exhibited a non-exhausted memory phenotype, whereas melanoma-reactive lymphocytes predominantly displayed an exhausted state that encompassed diverse levels of differentiation but rarely acquired memory properties. These exhausted phenotypes were observed both among clonotypes specific for public overexpressed melanoma antigens (shared across different tumours) or personal neoantigens (specific for each tumour). The recognition of such tumour antigens was provided by TCRs with avidities inversely related to the abundance of cognate targets in melanoma cells and proportional to the binding affinity of peptide–human leukocyte antigen (HLA) complexes. The persistence of TCR clonotypes in peripheral blood was negatively affected by the level of intratumoural exhaustion, and increased in patients with a poor response to immune checkpoint blockade, consistent with chronic stimulation mediated by residual tumour antigens. By revealing how the quality and quantity of tumour antigens drive the features of T cell responses within the tumour microenvironment, we gain insights into the properties of the anti-melanoma TCR repertoire.
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影响因子：
64.8
作者：
Im SJ;Hashimoto M;Gerner MY;Lee J;Kissick HT;Burger MC;Shan Q;Hale JS;Lee J;Nasti TH;Sharpe AH;Freeman GJ;Germain RN;Nakaya HI;Xue HH;Ahmed R
通讯作者：
Ahmed R
TCRdb：具有强大搜索功能的T细胞受体序列综合数据库
影响因子：
14.9
作者：
Chen SY;Yue T;Lei Q;Guo AY
通讯作者：
Guo AY
影响因子：
32.4
作者：
Abelin JG;Keskin DB;Sarkizova S;Hartigan CR;Zhang W;Sidney J;Stevens J;Lane W;Zhang GL;Eisenhaure TM;Clauser KR;Hacohen N;Rooney MS;Carr SA;Wu CJ
通讯作者：
Wu CJ
影响因子：
48
作者：
Stoeckius M;Hafemeister C;Stephenson W;Houck-Loomis B;Chattopadhyay PK;Swerdlow H;Satija R;Smibert P
通讯作者：
Smibert P
影响因子：
64.8
作者：
Simoni, Yannick;Becht, Etienne;Newell, Evan W.
通讯作者：
Newell, Evan W.