Faculty, Staff and Student Publications
Publication Date
12-1-2025
Journal
Oncoimmunology
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.
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.
Keywords
Humans, Carcinoma, Non-Small-Cell Lung, Male, Lung Neoplasms, Female, Immune Checkpoint Inhibitors, Middle Aged, Aged, Biomarkers, Tumor, B7-H1 Antigen, Mutation, Adult, Circulating Tumor DNA, Proteomics, Treatment Outcome, Neoplasm Metastasis, Blood-based biomarkers, Immunotherapy, digital spatial profiling, long-term responders, lung neoplasms, serum proteomics
DOI
10.1080/2162402X.2025.2469377
PMID
39991958
PMCID
PMC11853546
PubMedCentral® Posted Date
2-24-2025
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Genetic Phenomena Commons, Medical Genetics Commons, Oncology Commons