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有些免疫细胞更擅长杀死癌细胞,自然:特异感癌T胞不耗竭

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发表于 2021-9-19 11:28:16 | 显示全部楼层 |阅读模式
为什么有些免疫细胞更擅长杀死癌细胞?《自然》揭示提高免疫应答的关键

黑色素瘤中抗肿瘤 CD8 + T 细胞的表型、特异性和亲和力

特异感癌T胞不耗竭

学术经纬

2021/08/11

论文
论文标题:Phenotype, specificity and avidity of antitumour CD8+ T cells in melanoma
作者:Oliveira, Giacomo, Stromhaug, Kari, Klaeger, Susan, Kula, Tomasz, Frederick, Dennie T., Le, Phuong M., Forman, Juliet, Huang, Teddy, Li, Shuqiang, Zhang, Wandi, Xu, Qikai, Cieri, Nicoletta, Clauser, Karl R., Shukla, Sachet A., Neuberg, Donna, Justesen, Sune, MacBeath, Gavin, Carr, Steven A., Fritsch, Edward F., Hacohen, Nir, Sade-Feldman, Moshe, Livak, Kenneth J., Boland, Genevieve M., Ott, Patrick A., Keskin, Derin B., Wu, Catherine J.

期刊:Nature
发表时间:2021/07/21
数字识别码:10.1038/s41586-021-03704-y
摘要: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.

所属学科:
生物
免疫学
医学

(领研网导读 阿金)T细胞受体(TCRs)及其同源肿瘤抗源是抗肿瘤免疫应答的核心,但表型特征和TCR特征之间的关系并未得到完全阐释。本研究将TCRs抗原特异性和黑色素瘤浸润性淋巴细胞表型联系起来,发现肿瘤特异性塑造了肿瘤内CD8+T细胞的表达状态。具有肿瘤特异性TCR的T细胞大多呈现出“耗竭状态”的分子信号,表明T细胞功能下降,患者无法有效应答免疫检查点阻断的情况增加。该结果揭示了肿瘤环境内肿瘤抗原驱动T细胞应答特征的质量与数量,有助于加深对抗黑色素瘤TCR库特征的理解。





药明康德内容团队编辑  


免疫T细胞,依靠表面的T细胞受体(TCR)识别并攻击体内的病毒和异常细胞,例如癌细胞。然而,渗透到肿瘤组织中的T细胞表现不尽相同,有些擅长攻击癌细胞,有些却反应迟钝,甚至毫无反应。

在近期发表于《自然》杂志的一篇研究论文中,Catherine Wu教授与其丹娜-法伯癌症研究所(Dana-Farber Cancer Institute)和Broad研究所的同事,阐述了T细胞的行为表现与其表面TCR特性的关系。这项研究的发现为开发免疫应答更强的抗癌疗法提供了洞见。




在这项研究中,科学家们分析了多名黑色素瘤患者的活检样本和外周血样本。采用单细胞RNA测序和TCR测序,并结合表面蛋白的检测,他们将肿瘤浸润性T细胞的表型特征与其TCR的抗原特异性联系起来。

分析结果指出,肿瘤特异性塑造了浸润性T细胞的表达状态。具有肿瘤特异性TCR的T细胞,大多显现出“耗竭状态”(exhausted state)的分子信号。相反,非肿瘤反应性的T细胞表现出未耗竭的表型。




▲不同黑色素瘤患者的临床病程、治疗方法不同,研究人员对其样本进行了单细胞测序和TCR特异性的分析(图片来源:参考资料[1])




根据TCR提供的信息,出现耗竭状态的肿瘤浸润性T细胞,既包括了特异性识别过量表达的黑色素瘤抗原(即不同肿瘤共有的肿瘤抗原)的T细胞,也包括了靶向识别个体化肿瘤新生抗原(即每个肿瘤特有的抗原)的T细胞。耗竭状态意味着在肿瘤抗原的持续刺激下,这些T细胞功能下降。

血液循环中这类肿瘤浸润性耗竭T细胞的水平较高,与患者疾病状态持续直接相关。这些发现强调,对于癌症治疗,要产生有效的免疫应答,恢复正常的T细胞功能至关重要。




▲论文通讯作者Catherine Wu教授(图片来源:Dana-Farber Cancer Institute)


研究人员指出,通过鉴定抗肿瘤T细胞的特性,他们希望能够以产生具有有效抗肿瘤TCR和功能状态的T细胞为目的,开发新的治疗策略。


题图来源:123RF



参考资料:

[1] Oliveira G, et al. Phenotype, specificity and avidity of antitumour CD8+ T cells in melanoma. Nature. Published online July 21, 2021. DOI: 10.1038/s41586-021-03704-y.

[2] What makes some immune cells better at killing melanoma. Retrieved Aug. 10, 2021 from https://www.broadinstitute.org/n ... er-killing-melanoma



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