Bystander CD8+ T cells are abundant and phenotypically distinct in human tumour infiltrates
Bystander CD8+ T cells are abundant and phenotypically distinct in human tumour infiltrates
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DOI：
10.1038/s41586-018-0130-2
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发表时间：
2018-05-24
期刊：
影响因子：
64.8
通讯作者：
Newell, Evan W.
中科院分区：
文献类型：
--
作者：
Simoni, Yannick;Becht, Etienne;Newell, Evan W.
各种形式的免疫疗法，如检查点阻断免疫疗法，被证明在恢复T细胞介导的免疫应答方面是有效的，这些免疫应答可以导致显著和持续的临床应答，但仅在一些患者和癌症类型中有效（1-4）。患者和肿瘤可能对免疫治疗产生不可预测的反应，部分原因是个体肿瘤内和患者之间肿瘤浸润淋巴细胞（TIL）的免疫组成和表型特征的异质性（5，6）。尽管有证据表明肿瘤突变衍生的新抗原特异性T细胞在肿瘤控制中起作用（2，4，7 -10），但在大多数情况下，表型多样的肿瘤浸润性T细胞的抗原特异性在很大程度上是未知的。在这里，我们表明，人肺癌和结直肠癌CD 8（+）TIL不仅可以特异性肿瘤抗原（例如，新抗原），但也识别广泛的表位无关的癌症（如那些从EB病毒，人巨细胞病毒或流感病毒）。我们发现这些旁观者CD 8（+）TIL具有与肿瘤特异性细胞重叠的不同表型，但缺乏CD 39表达。在结直肠和肺肿瘤中，CD 8（+）TIL中缺乏CD 39定义了在肿瘤部位缺乏慢性抗原刺激标志的人群，支持将其分类为旁观者。不同患者的CD 39表达差异显著，一些患者主要为CD 39（-）CD 8（+）TIL。此外，CD 8（+）TIL中CD 39的表达频率与几个重要的临床参数相关，如肺肿瘤表皮生长因子受体的突变状态。我们的研究结果表明，并非所有的肿瘤浸润性T细胞都对肿瘤抗原具有特异性，并表明测量CD 39表达可能是量化或分离旁观者T细胞的直接方法。
Various forms of immunotherapy, such as checkpoint blockade immunotherapy, are proving to be effective at restoring T cell-mediated immune responses that can lead to marked and sustained clinical responses, but only in some patients and cancer types(1-4). Patients and tumours may respond unpredictably to immunotherapy partly owing to heterogeneity of the immune composition and phenotypic profiles of tumour-infiltrating lymphocytes (TILs) within individual tumours and between patients(5,6). Although there is evidence that tumour-mutation-derived neoantigen-specific T cells play a role in tumour control(2,4,7-10), in most cases the antigen specificities of phenotypically diverse tumour-infiltrating T cells are largely unknown. Here we show that human lung and colorectal cancer CD8(+) TILs can not only be specific for tumour antigens (for example, neoantigens), but also recognize a wide range of epitopes unrelated to cancer (such as those from Epstein-Barr virus, human cytomegalovirus or influenza virus). We found that these bystander CD8(+) TILs have diverse phenotypes that overlap with tumour-specific cells, but lack CD39 expression. In colorectal and lung tumours, the absence of CD39 in CD8(+) TILs defines populations that lack hallmarks of chronic antigen stimulation at the tumour site, supporting their classification as bystanders. Expression of CD39 varied markedly between patients, with some patients having predominantly CD39(-) CD8(+) TILs. Furthermore, frequencies of CD39 expression among CD8(+) TILs correlated with several important clinical parameters, such as the mutation status of lung tumour epidermal growth factor receptors. Our results demonstrate that not all tumour-infiltrating T cells are specific for tumour antigens, and suggest that measuring CD39 expression could be a straightforward way to quantify or isolate bystander T cells.