NK cell immune fitness stratifies small cell lung cancer into four functional states associated with clinical response.
14 affiliations
- 1Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy.
- 2Department of Pharmacy, School of Medicine, University of Naples Federico II, Naples, Italy.
- 3Institute of Biostructures and Bioimaging, National Research Council, Naples, Italy.
- 4A.O.U. Università Degli Studi Della Campania Luigi Vanvitelli, Naples, Italy.
- 5Department of Clinical Medicine and Surgery, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy.
- 6Department of Clinical Medicine and Surgery, University of Naples "Federico II,", Naples, 80131, Italy.
- 7Department of Experimental Medicine, University of Campania Luigi Vanvitelli, Caserta, Italy.
- 8Department of Experimental Medicine, University of Genoa, Genova, Italy.
- 9IRCCS Azienda Ospedaliera Universitaria, Genova, Italy.
- 10Bio-Organic Chemistry Unit, Institute of Biomolecular Chemistry, National Research Council, Naples, Italy.
- 11Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain.
- 12Department of Pulmonary Oncology, AORN Azienda Ospedaliera Dei Colli Monaldi, Naples, Italy.
- 13Department of Translational Medical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy.
- 14Department of Medicine, Surgery and Dentistry, "Scuola Medica Salernitana", University of Salerno, Baronissi, Italy.
Abstract
The reasons why some patients with small-cell lung cancer (SCLC) benefit from chemotherapy and immunotherapy, while others rapidly develop resistance, are still undefined. Despite improved outcomes with platinum-based chemotherapy combined with immune checkpoint inhibitors have been correlated to activation of the innate immunity, the role of immune cells as potential markers of response is incompletely understood. Here, we characterized the transcriptional and functional landscape of circulating natural killer (NK) cells in patients with SCLC at baseline and after cisplatin treatment, stratified by clinical response. By integrating transcriptomics, cytokine profiling, and high-dimensional flow cytometry, we identified distinct NK cell subsets and developed an NK immune-fitness signature validated in independent intratumoral cohorts. At baseline, responders exhibited strong interferon signaling, enrichment of CD16⁺ cytotoxic NK1 cells, and enhanced activation, correlating with prolonged progression-free survival, whereas non-responders showed a quiescent NK3-dominant profile. Following treatment, responders displayed further expansion of cytotoxic NK1 cells, while non-responders shifted toward reduced functional capacity. Analyses of immune infiltrate confirmed CD16, but not CD56, as a predictor of improved survival. Integration of effector and evasion programs defined four immunological states, with the infiltrated-active phenotype associated with the most favorable outcomes. These findings show that both baseline NK cell fitness and therapy-induced remodelling may shape clinical response and identify CD16⁺ NK cells as a potential clinically actionable biomarker to guide patient stratification and also inform NK-targeted new therapeutic strategies.
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BibTeX
@article{rosa2026cell,
title = {{NK cell immune fitness stratifies small cell lung cancer into four functional states associated with clinical response.}},
author = {Caterina De Rosa and Fabio Somma and Luisa Amato and Sara Capaldo and Faiz Ul Haq and Federica De Rosa and Francesca Iommelli and Viviana De Rosa and Concetta Tuccillo and Gaetano di Guida and Filippo Sepe and Alessandra Di Liello and Dilia Rea and Monica Grande and Anna Russo and Luigi Sapio and Angela Ragone and Silvio Naviglio and Marianna Capuano and Virginia Tirino and Emanuela Marcenaro and Simona Sivori and Giusi Barra and Valentina Gambardella and Giuseppe Viscardi and Marina Gilli and Fabiana Vitiello and Paola Maria Medusa and Alberto Servetto and Federica Sodano and Ferdinando De Vita and Fortunato Ciardiello and Floriana Morgillo and Federica Papaccio and Giuseppe Ercolano and Carminia Maria Della Corte},
journal = {The journal of liquid biopsy},
year = {2026},
month = oct,
doi = {10.1016/j.jlb.2026.100506},
url = {https://europepmc.org/article/MED/42894882},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - NK cell immune fitness stratifies small cell lung cancer into four functional states associated with clinical response.
AU - Caterina De Rosa
AU - Fabio Somma
AU - Luisa Amato
AU - Sara Capaldo
AU - Faiz Ul Haq
AU - Federica De Rosa
AU - Francesca Iommelli
AU - Viviana De Rosa
AU - Concetta Tuccillo
AU - Gaetano di Guida
AU - Filippo Sepe
AU - Alessandra Di Liello
AU - Dilia Rea
AU - Monica Grande
AU - Anna Russo
AU - Luigi Sapio
AU - Angela Ragone
AU - Silvio Naviglio
AU - Marianna Capuano
AU - Virginia Tirino
AU - Emanuela Marcenaro
AU - Simona Sivori
AU - Giusi Barra
AU - Valentina Gambardella
AU - Giuseppe Viscardi
AU - Marina Gilli
AU - Fabiana Vitiello
AU - Paola Maria Medusa
AU - Alberto Servetto
AU - Federica Sodano
AU - Ferdinando De Vita
AU - Fortunato Ciardiello
AU - Floriana Morgillo
AU - Federica Papaccio
AU - Giuseppe Ercolano
AU - Carminia Maria Della Corte
PY - 2026
DA - 2026/10/07
JO - The journal of liquid biopsy
DO - 10.1016/j.jlb.2026.100506
UR - https://europepmc.org/article/MED/42894882
AB - The reasons why some patients with small-cell lung cancer (SCLC) benefit from chemotherapy and immunotherapy, while others rapidly develop resistance, are still undefined. Despite improved outcomes with platinum-based chemotherapy combined with immune checkpoint inhibitors have been correlated to activation of the innate immunity, the role of immune cells as potential markers of response is incompletely understood. Here, we characterized the transcriptional and functional landscape of circulating natural killer (NK) cells in patients with SCLC at baseline and after cisplatin treatment, stratified by clinical response. By integrating transcriptomics, cytokine profiling, and high-dimensional flow cytometry, we identified distinct NK cell subsets and developed an NK immune-fitness signature validated in independent intratumoral cohorts. At baseline, responders exhibited strong interferon signaling, enrichment of CD16⁺ cytotoxic NK1 cells, and enhanced activation, correlating with prolonged progression-free survival, whereas non-responders showed a quiescent NK3-dominant profile. Following treatment, responders displayed further expansion of cytotoxic NK1 cells, while non-responders shifted toward reduced functional capacity. Analyses of immune infiltrate confirmed CD16, but not CD56, as a predictor of improved survival. Integration of effector and evasion programs defined four immunological states, with the infiltrated-active phenotype associated with the most favorable outcomes. These findings show that both baseline NK cell fitness and therapy-induced remodelling may shape clinical response and identify CD16⁺ NK cells as a potential clinically actionable biomarker to guide patient stratification and also inform NK-targeted new therapeutic strategies.
SN - 2950-1954
ER -