Tissue-resident memory features are linked to the magnitude of cytotoxic T cell responses in human lung cancer.
Tissue-resident memory features are linked to the magnitude of cytotoxic T cell responses in human lung cancer.
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DOI：
10.1038/ni.3775
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发表时间：
2017-08
影响因子：
30.5
通讯作者：
Ottensmeier CH
中科院分区：
文献类型：
--
作者：
Ganesan AP;Clarke J;Wood O;Garrido-Martin EM;Chee SJ;Mellows T;Samaniego-Castruita D;Singh D;Seumois G;Alzetani A;Woo E;Friedmann PS;King EV;Thomas GJ;Sanchez-Elsner T;Vijayanand P;Ottensmeier CH
增强细胞毒性T淋巴细胞（CTL）的抗肿瘤应答的疗法已显示出希望;然而，对目前可用的免疫抑制剂的临床应答差异很大，并且其分子基础尚不清楚。我们对来自未经治疗的肺癌患者的肿瘤浸润性CTL进行了转录组学分析，以确定与抗肿瘤免疫应答的稳健性相关的分子特征。我们观察到与T细胞抗原受体（TCR）活化相关的分子和免疫检查点分子（如4-1BB、PD-1和TIM-3）的表达存在相当大的异质性。具有高密度CTL的肿瘤显示与组织驻留记忆细胞（TRM细胞）（例如CD 103）连接的转录物的富集，并且来自CD 103 hi肿瘤的CTL显示增强的细胞毒性的特征。肿瘤中TRM细胞密度越大，预示着肺癌的生存结局越好，这种效应与CTL密度无关。在这里，我们定义了肿瘤浸润性CTL的“分子指纹”，并确定了免疫治疗的潜在新靶点。
Therapies that boost the anti-tumor responses of cytotoxic T lymphocytes (CTLs) have shown promise; however, clinical responses to the immunotherapeutic agents currently available vary considerably, and the molecular basis of this is unclear. We performed transcriptomic profiling of tumor-infiltrating CTLs from treatment-naive patients with lung cancer to define the molecular features associated with the robustness of anti-tumor immune responses. We observed considerable heterogeneity in the expression of molecules associated with activation of the T cell antigen receptor (TCR) and of immunological-checkpoint molecules such as 4-1BB, PD-1 and TIM-3. Tumors with a high density of CTLs showed enrichment for transcripts linked to tissue-resident memory cells (TRM cells), such as CD103, and CTLs from CD103hi tumors displayed features of enhanced cytotoxicity. A greater density of TRM cells in tumors was predictive of a better survival outcome in lung cancer, and this effect was independent of that conferred by CTL density. Here we define the ‘molecular fingerprint’ of tumor-infiltrating CTLs and identify potentially new targets for immunotherapy.
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