PDF(Pubmed)
Abstract：
Cancer-associated fibroblasts (CAFs) can exert their immunosuppressive effects by secreting various effectors that are involved in the regulation of tumor-infiltrating immune cells as well as other immune components in the tumor immune microenvironment (TIME), thereby promoting tumorigenesis, progression, metastasis, and drug resistance. Although a large number of studies suggest that CAFs play a key regulatory role in the development of head and neck squamous cell carcinoma (HNSCC), there are limited studies on the relevance of CAFs to the prognosis of HNSCC. In this study, we identified a prognostic signature containing eight CAF-related genes for HNSCC by univariate Cox analysis, lasso regression, stepwise regression, and multivariate Cox analysis. Our validation in primary cultures of CAFs from human HNSCC and four human HNSCC cell lines confirmed that these eight genes are indeed characteristic markers of CAFs. Immune cell infiltration differences analysis between high-risk and low-risk groups according to the eight CAF-related genes signature hinted at CAFs regulatory roles in the TIME, further revealing its potential role on prognosis. The signature of the eight CAF-related genes was validated in different independent validation cohorts and all showed that it was a valid marker for prognosis. The significantly higher overall survival (OS) in the low-risk group compared to the high-risk group was confirmed by Kaplan-Meier (K-M) analysis, suggesting that the signature of CAF-related genes can be used as a non-invasive predictive tool for HNSCC prognosis. The low-risk group had significantly higher levels of tumor-killing immune cell infiltration, as confirmed by CIBERSORT analysis, such as CD8+ T cells, follicular helper T cells, and Dendritic cells (DCs) in the low-risk group. In contrast, the level of infiltration of pro-tumor cells such as M0 macrophages and activated Mast cells (MCs) was lower. It is crucial to delve into the complex mechanisms between CAFs and immune cells to find potential regulatory targets and may provide new evidence for subsequently targeted immunotherapy. These results suggest that the signature of the eight CAF-related genes is a powerful indicator for the assessment of the TIME of HNSCC. It may provide a new and reliable potential indicator for clinicians to predict the prognosis of HNSCC, which may be used to guide treatment and clinical decision-making in HNSCC patients. Meanwhile, CAF-related genes are expected to become tumor biomarkers and effective targets for HNSCC.
摘要：
癌症相关成纤维细胞（CAFs）可以通过分泌各种效应子发挥其免疫抑制作用，这些效应子参与肿瘤浸润免疫细胞以及肿瘤免疫微环境（TIME）中的其他免疫成分的调节。从而促进肿瘤发生，programming,转移,和抗药性。尽管大量研究表明CAFs在头颈部鳞状细胞癌(HNSCC)的发生发展中起着关键的调节作用,关于CAFs与HNSCC预后相关性的研究有限。在这项研究中,我们通过单变量Cox分析确定了包含八个CAF相关基因的HNSCC的预后特征，套索回归，逐步回归，和多变量Cox分析。我们在来自人HNSCC和四种人HNSCC细胞系的CAF的原代培养物中的验证证实,这八个基因确实是CAF的特征性标志物。根据8个CAF相关基因特征分析高风险和低风险组之间的免疫细胞浸润差异，提示CAF在TIME中的调节作用，进一步揭示其对预后的潜在作用。在不同的独立验证队列中验证了8个CAF相关基因的特征，并且都表明它是预后的有效标记。通过Kaplan-Meier（K-M）分析证实了低危组的总生存率（OS）明显高于高危组，提示CAF相关基因的特征可用作HNSCC预后的非侵入性预测工具。低危组有明显较高水平的肿瘤杀伤免疫细胞浸润,正如CIBERSORT分析所证实的，如CD8+T细胞，滤泡辅助性T细胞,低风险组的树突状细胞（DCs）。相比之下,M0巨噬细胞和活化肥大细胞（MCs）等原瘤细胞的浸润水平较低。深入研究CAFs与免疫细胞之间的复杂机制对寻找潜在的调控靶点至关重要，并可能为后续靶向免疫治疗提供新的证据。这些结果表明，八个CAF相关基因的签名是评估HNSCC时间的有力指标。它可能为临床医生预测HNSCC的预后提供一个新的、可靠的潜在指标。可用于指导HNSCC患者的治疗和临床决策。同时,CAF相关基因有望成为肿瘤生物标志物和HNSCC的有效靶点。
