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研究揭示黑色素瘤中抗肿瘤CD8+T细胞的表型、特异性和亲和力
2021-07-25 14:02

美国哈佛医学院Catherine J. Wu课题组揭示黑色素瘤中抗肿瘤CD8+T细胞的表型、特异性和亲和力。相关论文于2021年7月21日在线发表在《自然》杂志上。

通过将T细胞受体(TCR)的抗原特异性和黑色素瘤浸润淋巴细胞的细胞表型在单细胞分辨率上联系起来,研究人员表明肿瘤特异性塑造了肿瘤内CD8+T细胞的表达状态。非肿瘤反应性T细胞富含病毒特异性,并表现出非衰竭性记忆表型,而黑色素瘤反应性淋巴细胞主要表现出衰竭状态,包括不同的分化水平,但很少获得记忆特性。这些衰竭表型在过量表达的黑色素瘤抗原(在不同肿瘤中共享)或个人新抗原(针对每个肿瘤)的克隆型中都能观察到。

对这种肿瘤抗原的识别是由TCR提供的,其亲和力与黑色素瘤细胞中同源靶标的丰度成反比,并与肽-人类白细胞抗原(HLA)复合物的结合亲和力成正比。外周血中TCR克隆型的持久性受到肿瘤内衰竭水平的负影响,并且在对免疫检查点阻断反应不佳的患者中有所增加,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内T细胞反应的特点,研究人员获得了对抗黑色素瘤TCR库特性的深入了解。

据介绍,TCR与其认知的肿瘤抗原之间的相互作用是抗肿瘤免疫反应的核心;然而,表型特征和TCR特性之间的关系没有得到很好的阐释。

附:英文原文

Title: Phenotype, specificity and avidity of antitumour CD8+ T cells in melanoma

Author: Giacomo Oliveira, Kari Stromhaug, Susan Klaeger, Tomasz Kula, Dennie T. Frederick, Phuong M. Le, Juliet Forman, Teddy Huang, Shuqiang Li, Wandi Zhang, Qikai Xu, Nicoletta Cieri, Karl R. Clauser, Sachet A. Shukla, Donna Neuberg, Sune Justesen, Gavin MacBeath, Steven A. Carr, Edward F. Fritsch, Nir Hacohen, Moshe Sade-Feldman, Kenneth J. Livak, Genevieve M. Boland, Patrick A. Ott, Derin B. Keskin, Catherine J. Wu

Issue&Volume: 2021-07-21

Abstract: Interactions between T cell receptors (TCRs) and their cognate tumour antigens are central to antitumour immune responses1,2,3; 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.

DOI: 10.1038/s41586-021-03704-y

Source: https://www.nature.com/articles/s41586-021-03704-y

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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