A comprehensive meta-analysis of tissue resident memory T cells and their roles in shaping immune microenvironment and patient prognosis in non-small cell lung cancer.

Tissue-resident memory T cells (T_RM) are a specialized subset of long-lived memory T cells that reside in peripheral tissues. However, the impact of T_RM-related immunosurveillance on the tumor-immune microenvironment (TIME) and tumor progression across various non-small-cell lung cancer (NSCLC) patient populations is yet to be elucidated. Our comprehensive analysis of multiple independent single-cell and bulk RNA-seq datasets of patient NSCLC samples generated reliable, unique T_RM signatures, through which we inferred the abundance of T_RM in NSCLC. We discovered that T_RM abundance is consistently positively correlated with CD4+ T helper 1 cells, M1 macrophages, and resting dendritic cells in the TIME. In addition, T_RM signatures are strongly associated with immune checkpoint and stimulatory genes and the prognosis of NSCLC patients. A T_RM-based machine learning model to predict patient survival was validated and an 18-gene risk score was further developed to effectively stratify patients into low-risk and high-risk categories, wherein patients with high-risk scores had significantly lower overall survival than patients with low-risk. The prognostic value of the risk score was independently validated by the Cancer Genome Atlas Program (TCGA) dataset and multiple independent NSCLC patient datasets. Notably, low-risk NSCLC patients with higher T_RM infiltration exhibited enhanced T-cell immunity, nature killer cell activation, and other TIME immune responses related pathways, indicating a more active immune profile benefitting from immunotherapy. However, the T_RM signature revealed low T_RM abundance and a lack of prognostic association among lung squamous cell carcinoma patients in contrast to adenocarcinoma, indicating that the two NSCLC subtypes are driven by distinct TIMEs. Altogether, this study provides valuable insights into the complex interactions between T_RM and TIME and their impact on NSCLC patient prognosis. The development of a simplified 18-gene risk score provides a practical prognostic marker for risk stratification. [ABSTRACT FROM AUTHOR]