Dai Liyuan, Huang Liling, Li Lin, Tang Le, Yao Jiarui, Shi Yuankai, Han Xiaohong
Department of Medical Oncology, Beijing Key Laboratory of Key Technologies for Early Clinical Trial Evaluation of Innovative Drugs for Major Diseases；National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital,, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China.
Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China.
BMC Cancer. 2025 Apr 23;25(1):763. doi: 10.1186/s12885-025-14148-2.
This study aims to evaluate cytokines as a prognostic biomarker in patients with advanced non-small cell lung cancer (aNSCLC) undergoing immunotherapy.
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.
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.
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.
本研究旨在评估细胞因子作为接受免疫治疗的晚期非小细胞肺癌（aNSCLC）患者的预后生物标志物。
采用流式荧光技术对接受免疫检查点抑制剂（ICI）治疗的aNSCLC患者中可溶性CD14（sCD14）和其他细胞因子的预后意义进行综合分析。在中国医学科学院肿瘤医院（CHCAMS），使用一个发现队列（n = 42）评估41种细胞因子在持久临床获益（DCB）组和无持久获益（NDB）组之间的差异表达。在多个独立队列中进一步验证其预后价值，包括CHCAMS中NSCLC的血浆蛋白测量（n = 109）、多重免疫荧光（mIF）（n = 22）和信使RNA数据集（n = 403）。
在发现队列中，7种细胞因子（CD14、CCL27、IL - 17A、表皮生长因子（EGF）、肿瘤坏死因子受体1（TNFR1）、胶质纤维酸性蛋白（GFAP）、几丁质酶3样蛋白1（CHI3L1））在DCB组和NDB组之间表现出差异表达。其中，DCB组中CD14、CCL27、IL - 17A和TNFR1显著升高，而NDB组中EGF、CHI3L1和趋化因子配体5（CCL5）更高。CD14在预测临床获益方面显示出较高的曲线下面积（AUC = 0.84）。功能富集分析表明，这些细胞因子参与关键免疫途径，包括炎症反应和丝裂原活化蛋白激酶（MAPK）信号传导。无进展生存期（PFS）的单因素COX分析显示，CD14（p < 0.001，风险比（HR）= 0.054 [0.014 - 0.219]）、CCL27（p < 正确答案：0.001，HR = 0.054 [0.015 - 0.196]）、IL - 17A（p < 0.001，HR = 0.110 [0.041 - 0.298]）和CCL5（p < 0.05，HR = 2.387 [1.023 - 5.570]）具有预后价值。在CHCAMS队列中的验证证实，通过mIF测量的CD14表达是PFS的预测指标（p < 0.05）。此外，在多个外部数据集（GSE126044、GSE135222、GSE136961和GSE218989）中，高CD14表达始终与较好的PFS相关。与肿瘤相比，发现CD14在各种正常组织类型中表达升高，特别是在肺腺癌和肺鳞状细胞癌中，表明其在免疫监视中的潜在作用。
sCD14是接受免疫治疗的aNSCLC患者有前景的预后生物标志物。血浆sCD14水平升高与改善的PFS和良好的免疫反应相关。
