3657 - Longitudinal Serum Proteomic Profiling of Radio-Immunotherapy Response in Oligometastatic Non-Small Cell Lung Cancer
Presenter(s)
Y. Wang1, M. Chen2, Q. Li3, and X. Li2; 1Sun Yat-sen University Cancer Center, Guangzhou, China, 2Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China, 3United Laboratory of Frontier Radiotherapy Technology of Sun Yat-sen University & Chinese Academy of Sciences Ion Medical Technology Co., Ltd, Guangzhou, China
Purpose/Objective(s): In oligometastatic non-small cell lung cancer (OM-NSCLC), the molecular determinants of differential response to radio-immunotherapy remain poorly characterized. We hypothesize that distinct, post-transcriptionally regulated proteomic dynamics underlie clinical sensitivity and resistance. This study aims to identify dynamic serum protein signatures that discriminate between therapy-sensitive and resistant OM-NSCLC patients, and to explore their mechanistic and clinical implications through integrative bioinformatics.
Materials/Methods: Longitudinal serum proteomic profiling was performed via mass spectrometry on 45 samples from 22 OM-NSCLC patients undergoing radio-immunotherapy, collected at three timepoints: pre-treatment, pre-radiotherapy, and post-radiotherapy. Patients were stratified into radio-immunotherapy sensitive (RIS, n=12) and resistant (RIR, n=10) groups. Differential expression analysis (adj.P.Val<0.1) was conducted within and between groups across timepoints using limma. Functional enrichment and Protein-Protein Interaction (PPI) network analysis were performed using clusterProfiler and the STRING database.
Results: We identified six hub proteins (SLC25A5, BAD, CREBBP, CD38, CALCR, ARF5) with baseline differential expression between RIS and RIR. PPI network analysis revealed these proteins form a tightly connected functional module, significantly enriched for mitochondrial apoptosis regulation (BAD, SLC25A5) and chromatin remodeling (CREBBP), suggesting coordinated dysregulation of distinct cellular compartments in treatment resistance. Longitudinal analysis unmasked profound heterogeneity: these hub proteins exhibited significant dynamic changes during treatment in RIS but attenuated changes in RIR, with CREBBP and BAD showing opposite directional trajectories between subgroups. Furthermore, we discovered a set of proteins with diametrically opposed treatment trajectories. Most notably, COPA (Coatomer Subunit Alpha) showed a striking 3.92 logFC differential (increased in RIS: +2.05, decreased in RIR: -1.87). Functional enrichment in RIS highlighted pathways including Fc gamma R-mediated phagocytosis. Critically, COPA expression trajectories showed 85% concordance with radiographic response at 3-month follow-up.
Conclusion: Our integrated analysis confirms that radio-immunotherapy response in OM-NSCLC is governed by divergent proteomic dynamics centered on a core network regulating apoptosis and epigenetics. The opposing trajectories of COPA, a key regulator of retrograde Golgi-to-ER transport, may reflect differential capacity for antigen presentation machinery maintenance between responders and non-responders, potentially explaining differential immune engagement. The high concordance between COPA dynamics and clinical outcome nominates it as a promising, non-invasive early dynamic biomarker.