组织驻留记忆性T（TRM）细胞为局部感染提供免疫防御，并且可以抑制癌症进展。然而，慢性炎症对TRM激活的影响程度以及肿瘤发生前存在于组织中的TRM细胞对人类癌症演化的影响尚不清楚。我们对从未吸烟者（NSs）和吸烟者（ESs）的健康肺部和肺癌进行了深入的分析，发现ES肺部的TRM样表型细胞具有增强的免疫监视证据。在临床前模型中，肿瘤特异性或旁观者TRM样细胞在肿瘤发生前存在，增强了免疫细胞的招募，导致通过MHC类I蛋白表达的丧失和对免疫检查点抑制剂的耐药性进行肿瘤免疫逃逸。在人类中，仅ES患者发生的肿瘤经历了克隆性免疫逃逸，与烟草相关的突变签名或致癌驱动因子无关。这些数据表明，肿瘤发展前增强的TRM样活性塑造了肿瘤免疫原性的演化，并可以影响免疫治疗结果。

Tissue-resident memory T (TRM) cells provide immune defense against local infection and can inhibit cancer progression. However, it is unclear to what extent chronic inflammation impacts TRM activation and whether TRM cells existing in tissues before tumor onset influence cancer evolution in humans. We performed deep profiling of healthy lungs and lung cancers in never-smokers (NSs) and ever-smokers (ESs), finding evidence of enhanced immunosurveillance by cells with a TRM-like phenotype in ES lungs. In preclinical models, tumor-specific or bystander TRM-like cells present prior to tumor onset boosted immune cell recruitment, causing tumor immune evasion through loss of MHC class I protein expression and resistance to immune checkpoint inhibitors. In humans, only tumors arising in ES patients underwent clonal immune evasion, unrelated to tobacco-associated mutagenic signatures or oncogenic drivers. These data demonstrate that enhanced TRM-like activity prior to tumor development shapes the evolution of tumor immunogenicity and can impact immunotherapy outcomes.Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.