Molecular and immunological features associated with long-term benefits in metastatic NSCLC patients undergoing immune checkpoint blockade
Introduction Immunotherapy is firmly established as a treatment regimen in various solid tumors, driven by its exceptional benefits in a selected group of patients. Despite widespread adoption of immune checkpoint blockade (ICB) across diverse solid tumors, the quest for a clinically informative bio...
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Taylor & Francis Group
2025-12-01
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| Series: | OncoImmunology |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/2162402X.2025.2469377 |
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| author | Pedro Rocha Rafael Bach Laura Masfarré Sharia Hernandez Nil Navarro-Gorro Adrià Rossell Xavier Villanueva Mario Giner Ignacio Sanchéz Miguel Galindo Raúl Del Rey-Vergara Albert Iñañez Beatriz Sanchéz-Espiridion Wei Lu Ariadna Acedo-Terrades Pau Berenguer-Molins Albert Sánchez-Font Roberto Chalela Victor Curull Álvaro Taus Max Hardy-Werbin Mark Sausen Andrew Georgiadis James White Jennifer B Jackson Laura Moliner Sergi Clavé Beatriz Bellosillo Ana Rovira Ignacio Wistuba Luisa M Solis Soto Júlia Perera-Bel Edurne Arriola |
| author_facet | Pedro Rocha Rafael Bach Laura Masfarré Sharia Hernandez Nil Navarro-Gorro Adrià Rossell Xavier Villanueva Mario Giner Ignacio Sanchéz Miguel Galindo Raúl Del Rey-Vergara Albert Iñañez Beatriz Sanchéz-Espiridion Wei Lu Ariadna Acedo-Terrades Pau Berenguer-Molins Albert Sánchez-Font Roberto Chalela Victor Curull Álvaro Taus Max Hardy-Werbin Mark Sausen Andrew Georgiadis James White Jennifer B Jackson Laura Moliner Sergi Clavé Beatriz Bellosillo Ana Rovira Ignacio Wistuba Luisa M Solis Soto Júlia Perera-Bel Edurne Arriola |
| author_sort | Pedro Rocha |
| collection | DOAJ |
| description | Introduction Immunotherapy is firmly established as a treatment regimen in various solid tumors, driven by its exceptional benefits in a selected group of patients. Despite widespread adoption of immune checkpoint blockade (ICB) across diverse solid tumors, the quest for a clinically informative biomarker for long-term benefit remains unmet.Methods A total of 49 patients with metastatic NSCLC treated with ICB were included. Long-term (LTR) and short-term responders (STR) were defined as those with a response to ICB lasting more than 24 months or less than 6 months, respectively. Longitudinal blood specimens were collected before ICB treatment initiation and early-on treatment. Plasma ctDNA next-generation sequencing panel (NGS) and serum proteomics were performed. GeoMx DSP on baseline tumor tissue was performed in a subset of patients.Results Our analysis revealed specific characteristics of LTR compared with STR, namely higher PD-L1 in tumor cells (p = 0.005) and higher incidence of irAEs (p = 0.001). Genomic features associated with lack of benefit from ICB included co-occurring mutations in KRAS/STK11 and TP53/KMT2D (p < 0.05). At a baseline, LTR patients exhibited higher serum levels of proteins related with apoptosis (CASP8, PRKRA), chemotaxis, immune proteasome, processing of MHC class I (S100A4, PSMD9, RNF41) and immune homeostasis (HAVCR1, ARG1) (p < 0.05). Protein spatial profiling of tumor samples showed higher levels of proteins linked with the presence of immune cells (CD45), T cells (CD8), antigen presentation (HLA-DR) and immune regulation proteins (PD-L1, IDO1) within the tumor and tumor stroma component (p < 0.05) in LTR patients. Serum longitudinal analysis identified a set of proteins that presented distinct dynamics in LTR compared to STR, making them interesting candidates to evaluate as early predictors of treatment efficacy.Conclusions Our multimodal analysis of patients with metastatic NSCLC treated with ICB identified clinicopathological and immunological features associated with long-term benefits. The presence of preexisting antitumor immunity emerged as a strong predictor of long-term benefits, providing insights for potential biomarkers and therapeutic strategies for enhancing ICB outcomes in metastatic NSCLC. |
| format | Article |
| id | doaj-art-6d2c3a91c79e45d7af299dbe47d7ce1c |
| institution | OA Journals |
| issn | 2162-402X |
| language | English |
| publishDate | 2025-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | OncoImmunology |
| spelling | doaj-art-6d2c3a91c79e45d7af299dbe47d7ce1c2025-08-20T01:56:56ZengTaylor & Francis GroupOncoImmunology2162-402X2025-12-0114110.1080/2162402X.2025.2469377Molecular and immunological features associated with long-term benefits in metastatic NSCLC patients undergoing immune checkpoint blockadePedro Rocha0Rafael Bach1Laura Masfarré2Sharia Hernandez3Nil Navarro-Gorro4Adrià Rossell5Xavier Villanueva6Mario Giner7Ignacio Sanchéz8Miguel Galindo9Raúl Del Rey-Vergara10Albert Iñañez11Beatriz Sanchéz-Espiridion12Wei Lu13Ariadna Acedo-Terrades14Pau Berenguer-Molins15Albert Sánchez-Font16Roberto Chalela17Victor Curull18Álvaro Taus19Max Hardy-Werbin20Mark Sausen21Andrew Georgiadis22James White23Jennifer B Jackson24Laura Moliner25Sergi Clavé26Beatriz Bellosillo27Ana Rovira28Ignacio Wistuba29Luisa M Solis Soto30Júlia Perera-Bel31Edurne Arriola32Medical Oncology Department, Hospital del Mar, Barcelona, SpainMedical Oncology Department, Hospital del Mar, Barcelona, SpainMedical Oncology Department, Hospital del Mar, Barcelona, SpainDepartment of Translational Molecular Pathology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USAMedical Oncology Department, Hospital del Mar, Barcelona, SpainMedical Oncology Department, Hospital del Mar, Barcelona, SpainMedical Oncology Department, Hospital del Mar, Barcelona, SpainPathology Department, Hospital del Mar, Barcelona, SpainPathology Department, Hospital del Mar, Barcelona, SpainCancer Research Program, Hospital del Mar Research Institute, Barcelona, SpainCancer Research Program, Hospital del Mar Research Institute, Barcelona, SpainCancer Research Program, Hospital del Mar Research Institute, Barcelona, SpainDepartment of Translational Molecular Pathology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USADepartment of Translational Molecular Pathology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USACancer Research Program, Hospital del Mar Research Institute, Barcelona, SpainMARData, Hospital del Mar Research Institute, Barcelona, SpainPulmonology Department, Hospital del Mar, Barcelona, SpainPulmonology Department, Hospital del Mar, Barcelona, SpainPulmonology Department, Hospital del Mar, Barcelona, SpainMedical Oncology Department, Hospital del Mar, Barcelona, SpainMedical Oncology Department, Hospital del Mar, Barcelona, SpainLabcorp Oncology, Baltimore, MD, USALabcorp Oncology, Baltimore, MD, USALabcorp Oncology, Baltimore, MD, USALabcorp Oncology, Baltimore, MD, USAMedical Oncology Department, ICO, Barcelona, SpainPathology Department, Hospital del Mar, Barcelona, SpainPathology Department, Hospital del Mar, Barcelona, SpainMedical Oncology Department, Hospital del Mar, Barcelona, SpainDepartment of Translational Molecular Pathology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USADepartment of Translational Molecular Pathology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USAMARData, Hospital del Mar Research Institute, Barcelona, SpainMedical Oncology Department, Hospital del Mar, Barcelona, SpainIntroduction Immunotherapy is firmly established as a treatment regimen in various solid tumors, driven by its exceptional benefits in a selected group of patients. Despite widespread adoption of immune checkpoint blockade (ICB) across diverse solid tumors, the quest for a clinically informative biomarker for long-term benefit remains unmet.Methods A total of 49 patients with metastatic NSCLC treated with ICB were included. Long-term (LTR) and short-term responders (STR) were defined as those with a response to ICB lasting more than 24 months or less than 6 months, respectively. Longitudinal blood specimens were collected before ICB treatment initiation and early-on treatment. Plasma ctDNA next-generation sequencing panel (NGS) and serum proteomics were performed. GeoMx DSP on baseline tumor tissue was performed in a subset of patients.Results Our analysis revealed specific characteristics of LTR compared with STR, namely higher PD-L1 in tumor cells (p = 0.005) and higher incidence of irAEs (p = 0.001). Genomic features associated with lack of benefit from ICB included co-occurring mutations in KRAS/STK11 and TP53/KMT2D (p < 0.05). At a baseline, LTR patients exhibited higher serum levels of proteins related with apoptosis (CASP8, PRKRA), chemotaxis, immune proteasome, processing of MHC class I (S100A4, PSMD9, RNF41) and immune homeostasis (HAVCR1, ARG1) (p < 0.05). Protein spatial profiling of tumor samples showed higher levels of proteins linked with the presence of immune cells (CD45), T cells (CD8), antigen presentation (HLA-DR) and immune regulation proteins (PD-L1, IDO1) within the tumor and tumor stroma component (p < 0.05) in LTR patients. Serum longitudinal analysis identified a set of proteins that presented distinct dynamics in LTR compared to STR, making them interesting candidates to evaluate as early predictors of treatment efficacy.Conclusions Our multimodal analysis of patients with metastatic NSCLC treated with ICB identified clinicopathological and immunological features associated with long-term benefits. The presence of preexisting antitumor immunity emerged as a strong predictor of long-term benefits, providing insights for potential biomarkers and therapeutic strategies for enhancing ICB outcomes in metastatic NSCLC.https://www.tandfonline.com/doi/10.1080/2162402X.2025.2469377Blood-based biomarkersdigital spatial profilingImmunotherapylong-term responderslung neoplasmsserum proteomics |
| spellingShingle | Pedro Rocha Rafael Bach Laura Masfarré Sharia Hernandez Nil Navarro-Gorro Adrià Rossell Xavier Villanueva Mario Giner Ignacio Sanchéz Miguel Galindo Raúl Del Rey-Vergara Albert Iñañez Beatriz Sanchéz-Espiridion Wei Lu Ariadna Acedo-Terrades Pau Berenguer-Molins Albert Sánchez-Font Roberto Chalela Victor Curull Álvaro Taus Max Hardy-Werbin Mark Sausen Andrew Georgiadis James White Jennifer B Jackson Laura Moliner Sergi Clavé Beatriz Bellosillo Ana Rovira Ignacio Wistuba Luisa M Solis Soto Júlia Perera-Bel Edurne Arriola Molecular and immunological features associated with long-term benefits in metastatic NSCLC patients undergoing immune checkpoint blockade OncoImmunology Blood-based biomarkers digital spatial profiling Immunotherapy long-term responders lung neoplasms serum proteomics |
| title | Molecular and immunological features associated with long-term benefits in metastatic NSCLC patients undergoing immune checkpoint blockade |
| title_full | Molecular and immunological features associated with long-term benefits in metastatic NSCLC patients undergoing immune checkpoint blockade |
| title_fullStr | Molecular and immunological features associated with long-term benefits in metastatic NSCLC patients undergoing immune checkpoint blockade |
| title_full_unstemmed | Molecular and immunological features associated with long-term benefits in metastatic NSCLC patients undergoing immune checkpoint blockade |
| title_short | Molecular and immunological features associated with long-term benefits in metastatic NSCLC patients undergoing immune checkpoint blockade |
| title_sort | molecular and immunological features associated with long term benefits in metastatic nsclc patients undergoing immune checkpoint blockade |
| topic | Blood-based biomarkers digital spatial profiling Immunotherapy long-term responders lung neoplasms serum proteomics |
| url | https://www.tandfonline.com/doi/10.1080/2162402X.2025.2469377 |
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