NK cell immune fitness stratifies small cell lung cancer into four functional states associated with clinical response
Year: 2026
Type: article
Study design: Observational Study
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 remodeling 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.
Source: The Journal of Liquid Biopsy
Authors: Caterina De Rosa, Fabio Somma, Luisa Amato, Sara Capaldo, Faiz Ul Haq, Federica De Rosa, Francesca Iommelli, Viviana De Rosa, Concetta Tuccillo, Gaetano di Guida, Filippo Sepe, Alessandra Di Liello, Dilia Rea, Monica Grande, Anna Russo, Luigi Sapio, Angela Ragone, Silvio Naviglio, Marianna Capuano, Virginia Tirino, Emanuela Marcenaro, Simona Sivori, Giusi Barra, Valentina Gambardella, Giuseppe Viscardi, Marina Gilli, Fabiana Vitiello, Paola Maria Medusa, Alberto Servetto, Federica Sodano, Ferdinando De Vita, Fortunato Ciardiello, Floriana Morgillo, Federica Papaccio, Giuseppe Ercolano, Carminia Maria Della Corte
Institutions: University of Campania "Luigi Vanvitelli", University of Naples Federico II, Institute of Biostructure and Bioimaging, National Research Council, Federico II University Hospital, Ospedale Policlinico San Martino, University of Genoa, Universitat de València, INCLIVA Health Research Institute, Ospedale Monaldi, University of Salerno
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,080
OpenAlex ID: W7166448604