Molecular and immunological features associated with long-term benefits in metastatic NSCLC patients undergoing immune checkpoint blockade
OncoImmunology, 2025
Rocha P., Bach R., Masfarré L., Hernandez S., Navarro-Gorro N., Rossell A., Villanueva X., Giner M., Sanchéz I., Galindo M., Del Rey-Vergara R., Iñañez A., Sanchéz-Espiridion B., Lu W., Acedo-Terrades A., Berenguer-Molins P., Sánchez-Font A., Chalela R., Curull V., Taus ?., Hardy-Werbin M., Sausen M., Georgiadis A., White J., Jackson J., Moliner L., Clavé S., Bellosillo B., Rovira A., Wistuba I., Soto L., Perera-Bel J., Arriola E.
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
Oncology Immunotherapy | Patient Stratification | Serum |  Olink Explore 3072/384 |
Abstract
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.ConclusionsOur 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.