Pretreatment plasma sCD14 as a prognostic indicator in advanced non-small cell lung cancer patients undergoing immunotherapy.

BACKGROUND: This study aims to evaluate cytokines as a prognostic biomarker in patients with advanced non-small cell lung cancer (aNSCLC) undergoing immunotherapy. METHODS: A comprehensive analysis was conducted to assess the prognostic significance of sCD14 and other cytokines in aNSCLC patients receiving immune checkpoint inhibitors (ICIs) using flow fluorescence. A discovery cohort (n = 42) was used to evaluate the differential expression of 41 cytokines between durable clinical benefit (DCB) and no durable benefit (NDB) groups in Cancer Hospital, Chinese Academy of Medical Sciences (CHCAMS). The prognostic value was further validated in multiple independent cohorts, including plasma protein measurements (n = 109), multiplex immunofluorescence (mIF) (n = 22), and messenger RNA datasets (n = 403) of NSCLC in CHCAMS. RESULTS: In the discovery cohort, 7 cytokines (CD14, CCL27, IL-17 A, EGF, TNFR1, GFAP, CHI3L1) exhibited differential expression between the DCB and NDB groups. Among these, CD14, CCL27, IL-17 A, and TNFR1 were significantly elevated in the DCB group, while EGF, CHI3L1, and CCL5 were higher in the NDB group. CD14 showed a high area under the curve (AUC = 0.84) for predicting clinical benefit. Functional enrichment analysis indicated that these cytokines are involved in key immune pathways, including the inflammatory response and MAPK signaling. Univariate COX for progression-free survival (PFS) analysis demonstrated prognostic value for CD14 (p < 0.001, HR = 0.054 [0.014-0.219]), CCL27 (p < 0.001, HR = 0.054 [0.015-0.196]), IL-17 A (p < 0.001, HR = 0.110 [0.041-0.298]), and CCL5 (p < 0.05, HR = 2.387 [1.023-5.570]). Validation in the CHCAMS cohort confirmed that CD14 expression, measured via mIF, was a predictor of PFS (p < 0.05). Furthermore, high CD14 expression was consistently associated with superior PFS across multiple external datasets (GSE126044, GSE135222, GSE136961, and GSE218989). CD14 expression was found to be elevated in various normal tissue types, particularly in lung adenocarcinoma and lung squamous cell carcinoma, compared to tumors, indicating its potential role in immune surveillance. CONCLUSION: sCD14 is a promising prognostic biomarker for aNSCLC patients undergoing immunotherapy. Elevated plasma sCD14 levels are associated with improved PFS and a favorable immune response.