The T cell differentiation landscape is shaped by tumour mutations in lung cancer
The T cell differentiation landscape is shaped by tumour mutations in lung cancer
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DOI：
10.1038/s43018-020-0066-y
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发表时间：
2020-05-01
期刊：
影响因子：
22.7
通讯作者：
Quezada, Sergio A.
中科院分区：
文献类型：
--
作者：
Ghorani, Ehsan;Reading, James L.;Quezada, Sergio A.
肿瘤突变负荷（TMB）预测非小细胞肺癌（NSCLC）的免疫治疗结果，与肿瘤新抗原的免疫识别一致。然而，持续的抗原暴露对T细胞功能是有害的。TMB如何影响未治疗肿瘤中的CD4和CD8 T细胞分化以及这是否影响患者预后尚不清楚。在这里，我们配对高维流式细胞术、外显子组、单细胞和大量RNA测序来自切除的、未经治疗的非小细胞肺癌患者，以检查这些关系。TMB与全室T细胞分化偏斜有关，其特征是表达tcf7的祖细胞样CD4 T细胞的缺失，以及功能失调的CD8和CD4 T细胞亚群的丰度增加，这些亚群与新抗原反应性CD8 T细胞具有很强的表型和转录相似性。在肺癌和其他癌症队列中，从祖细胞样再分配到功能失调状态的基因特征与生存率低有关。这些群体的单细胞特征为非小细胞肺癌的治疗操作提供了潜在的策略。
Tumour mutational burden (TMB) predicts immunotherapy outcome in non-small cell lung cancer (NSCLC), consistent with immune recognition of tumour neoantigens. However, persistent antigen exposure is detrimental for T cell function. How TMB affects CD4 and CD8 T cell differentiation in untreated tumours and whether this affects patient outcomes is unknown. Here, we paired high-dimensional flow cytometry, exome, single-cell and bulk RNA sequencing from patients with resected, untreated NSCLC to examine these relationships. TMB was associated with compartment-wide T cell differentiation skewing, characterized by loss of TCF7-expressing progenitor-like CD4 T cells, and an increased abundance of dysfunctional CD8 and CD4 T cell subsets with strong phenotypic and transcriptional similarity to neoantigen-reactive CD8 T cells. A gene signature of redistribution from progenitor-like to dysfunctional states was associated with poor survival in lung and other cancer cohorts. Single-cell characterization of these populations informs potential strategies for therapeutic manipulation in NSCLC.