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.

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 如何影响未经治疗的肿瘤中的 CD4 和 CD8 T 细胞分化，以及这是否会影响患者的预后尚不清楚。在这里，我们将来自已切除、未经治疗的 NSCLC 患者的高维流式细胞术、外显子组、单细胞和大量 RNA 测序配对，以检查这些关系。TMB 与全区室 T 细胞分化偏斜相关，其特征是表达 TCF7 的祖细胞样 CD4 T 细胞丢失，以及功能失调的 CD8 和 CD4 T 细胞亚群的丰度增加，这些细胞亚群与新抗原反应性 CD8 T 有很强的表型和转录相似性细胞。从类祖细胞状态重新分布到功能失调状态的基因特征与肺癌和其他癌症队列的生存率低有关。这些群体的单细胞表征为 NSCLC 的治疗操作提供了潜在策略。