Tumor-infiltrating natural killer cell profiling for therapeutic stratification in patients with resectable non–small cell lung cancer
Year: 2026
Type: article
Study design: Observational Study
Abstract: OBJECTIVE: Neoadjuvant chemoimmunotherapy has improved outcomes in resectable non-small cell lung cancer, yet its real-world implementation is often challenged by surgical delays, immune-mediated fibrosis, and postoperative complications. Smokers with non-small cell lung cancer, despite a high risk for surgical morbidity, show enhanced responses to neoadjuvant chemoimmunotherapy. This study aimed to identify smoking-associated immune cell determinants that could guide treatment strategies. METHODS: Single-cell RNA sequencing was performed on 61 lung tissues from nonsmokers and smokers to identify smoking-related immune compositions. The single-cell RNA sequencing data from 19 invasive lung adenocarcinomas were used to validate their presence in the tumor-immune microenvironment. Bulk RNA sequencing data from 102 patients with resected non-small cell lung cancer and 24 patients with non-small cell lung cancer treated with neoadjuvant chemoimmunotherapy followed by surgery were used for in silico cellular deconvolution and outcome analyses. RESULTS: Among 135 lung cellular phenotypes, 2 natural killer cell subsets were strongly associated with smoking and chronic obstructive pulmonary disease severity. "Stress-responsive" natural killer cells exhibited immature features and cytokine-responsive features, and "adaptive and immunoregulatory natural killer" cells showed mature features and elevated multiple immune checkpoint expression. High intratumoral "stress-responsive" natural killer cells correlated with improved survival after surgery, particularly in current smokers. Conversely, tumors with low "stress-responsive" natural killer and high "adaptive and immunoregulatory natural killer" cells responded more favorably to neoadjuvant chemoimmunotherapy. CONCLUSIONS: Intratumoral natural killer cell phenotyping may aid in therapeutic stratification in patients with non-small cell lung cancer. "Stress-responsive" natural killer cell preservation predicts benefit from up-front surgery, whereas "adaptive and immunoregulatory natural killer" cell enrichment indicates improved response to neoadjuvant chemoimmunotherapy. These natural killer cell profiles may help optimize treatment by balancing therapeutic benefit and risk.
Authors: Atsushi Ito, Sung Wook Kang, Hee-Jin Jang, Ji Seon Shim, Claire Lee, Priyanka Ranchod, Gena Lee, Sonali Mitra, Jiyeon Jeon, Ayu H. Syarif, Yun Zhang, Jinyoung Byun, Younghun Han, Joshua Malo, Meera Patel, R. Taylor Ripley, Shawn S. Groth, Farrah Kheradmand, Bryan M. Burt, Francesca Polverino, Christopher I. Amos, Hyun-Sung Lee
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,500
Funders: U.S. Department of Defense, Cancer Prevention and Research Institute of Texas, Baylor College of Medicine, Diana Helis Henry Medical Research Foundation, National Institutes of Health, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of Allergy and Infectious Diseases, Common Fund
Awards: G1074394171, Comprehensive Cancer Epigenomics Core Facility, Recruitment of Established Investigators, G1700143112, G32461210, Integrative Analysis of Lung Cancer Etiology and Risk, G4065300843, G418187648, G4182736573, NOVEL HUMORAL AND CELLULAR BIOMARKERS OF AUTOIMMUNE DISEASES CAUSED BY IMMUNOTHERAPY, G5201123904, G5616238085, Spatial Profiling of Tumor-Immune Microenvironment by Multiplexed Single- Cell Imaging Mass Cytometry, G5968421958, G6115334031, B cell-adaptive Immune Profile in Emphysema-predominant COPD, G7854359243, G815075167, G8919627261, Proteomic determinants of response to checkpoint blockade in malignant pleural mesothelioma, Baylor College of Medicine Cancer Center - Cancer Center Support Grant, Heterogeneous Genetic Architecture in Lung Cancer Risk, Protective effects of metformin against cigarette smoke-induced lung pathologies via regulation of fatty acids metabolism
OpenAlex ID: W7133490554