Journal Article

Dissecting non-small cell lung cancer (NSCLC) with blood proteomics—from surgical to immunotherapeutic responses

Mendes, Gwendoline, Monkman, James, Adams, Mark N., Lawler, Clara, O’Leary, Connor, Mullally, William, Wijerathna-Yapa, Akila, Kilgallon, Aaron, Mansfield, James, Warkiani, Majid E., Kulasinghe, Arutha, O’Byrne, Ken, Yaghoubi Naei, Vahid, Dutta, Sanjay, Hedou, Julien

2026

Overview

NSCLC remains a leading cause of cancer-related mortality, with limited biomarkers to guide surgical and immunotherapeutic intervention. This study leveraged two complementary plasma proteomics platforms, SomaScan (7596 proteins) and NULISA (250 inflammation-related proteins) to profile 87 timepoints from 56 NSCLC patients, collected pre- and post-surgery and pre- and post-ICI therapy. Robust biomarker selection used adaptive Lasso regression and the Stabl algorithm, with inter- and intra-cohort validation via orthogonal nELISA proteomics. Twenty-one differentially detectable plasma proteins were identified across treatment contexts. Surgical resection induced measurable proteomic changes: non-recurrent patients had higher circulating MUC16 and lower IL36G post-surgery, while recurrent patients showed elevated COX7A2L, FGF19, and SPOCK2, alongside lower FCER2, FCRLA, and SLITRK2. Among ICI-treated patients, responders had lower baseline levels of IL-6, CCL19, IL-2RA, CD200R1, CRP, LIF, PDCD1, CCL7, and SPP1, implicating systemic inflammation and immune regulation in treatment sensitivity. CEACAM5, PTX3, FGF23, and AREG were elevated in patients with worse clinical outcomes and poorer overall survival. MUC16, IL36G, CCL19, and IL-6 were independently validated by nELISA. Cross-platform comparison highlighted the complementary strengths of SomaScan's broad proteomic coverage and NULISA's sensitivity for low-abundance proteins. This integrated approach reveals distinct plasma signatures associated with surgical recurrence, ICI response, and prognosis in NSCLC.