Department of Epidemiology and Health Statistics, Dalian Medical University, Dalian 116044, China.
Int J Mol Sci. 2023 Aug 25;24(17):13209. doi: 10.3390/ijms241713209.
Cancer immune escape is associated with the metabolic reprogramming of the various infiltrating cells in the tumor microenvironment (TME), and combining metabolic targets with immunotherapy shows great promise for improving clinical outcomes. Among all metabolic processes, lipid metabolism, especially fatty acid metabolism (FAM), plays a major role in cancer cell survival, migration, and proliferation. However, the mechanisms and functions of FAM in the tumor immune microenvironment remain poorly understood. We screened 309 fatty acid metabolism-related genes (FMGs) for differential expression, identifying 121 differentially expressed genes. Univariate Cox regression models in The Cancer Genome Atlas (TCGA) database were then utilized to identify the 15 FMGs associated with overall survival. We systematically evaluated the correlation between FMGs' modification patterns and the TME, prognosis, and immunotherapy. The FMGsScore was constructed to quantify the FMG modification patterns using principal component analysis. Three clusters based on FMGs were demonstrated in breast cancer, with three patterns of distinct immune cell infiltration and biological behavior. An FMGsScore signature was constructed to reveal that patients with a low FMGsScore had higher immune checkpoint expression, higher immune checkpoint inhibitor (ICI) scores, increased immune microenvironment infiltration, better survival advantage, and were more sensitive to immunotherapy than those with a high FMGsScore. Finally, the expression and function of the signature key gene were examined by in vitro experiments. This study significantly demonstrates the substantial impact of FMGs on the immune microenvironment of breast cancer, and that FMGsScores can be used to guide the prediction of immunotherapy efficacy in breast cancer patients. In vitro experiments, knockdown of the gene resulted in reduced proliferation and migration of MCF-7 and MDA-MB-231 cell lines.
癌症免疫逃逸与肿瘤微环境（TME）中各种浸润细胞的代谢重编程有关，将代谢靶点与免疫疗法相结合，为改善临床结果带来了巨大的希望。在所有代谢过程中，脂质代谢，特别是脂肪酸代谢（FAM），在癌细胞的存活、迁移和增殖中起着主要作用。然而，FAM 在肿瘤免疫微环境中的机制和功能仍知之甚少。我们筛选了 309 个脂肪酸代谢相关基因（FMGs）的差异表达，确定了 121 个差异表达基因。然后，我们利用癌症基因组图谱（TCGA）数据库中的单变量 Cox 回归模型，鉴定了与总生存期相关的 15 个 FMGs。我们系统地评估了 FMG 修饰模式与 TME、预后和免疫治疗的相关性。使用主成分分析构建了 FMGsScore 来量化 FMG 的修饰模式。在乳腺癌中，基于 FMGs 鉴定出三个聚类，具有三种不同免疫细胞浸润和生物学行为的模式。构建了 FMGsScore 标志物，以揭示 FMGsScore 低的患者具有更高的免疫检查点表达、更高的免疫检查点抑制剂（ICI）评分、增加的免疫微环境浸润、更好的生存优势，并且比 FMGsScore 高的患者对免疫治疗更敏感。最后，通过体外实验检验了特征基因的表达和功能。本研究显著证明了 FMGs 对乳腺癌免疫微环境的巨大影响，并且 FMGsScores 可以用于指导乳腺癌患者免疫治疗疗效的预测。体外实验，基因的敲低导致 MCF-7 和 MDA-MB-231 细胞系的增殖和迁移减少。
