Wang Xinan, Lin Li, Zhang Xue, Zhang Minghui, Sun Zhuo, Yang Yichen, Zhang Xiuna, Yuan Yonghui, Zhang Yong, Chen Hao, Wen Ti
Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning, China.
Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Hospital of China Medical University, Shenyang, Liaoning, China.
Front Immunol. 2024 Dec 24;15:1501009. doi: 10.3389/fimmu.2024.1501009. eCollection 2024.
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, with the worst prognosis among all subtypes. The impact of distinct cell subpopulations within the tumor microenvironment (TME) on TNBC patient prognosis has yet to be clarified.
Utilizing single-cell RNA sequencing (scRNA-seq) integrated with bulk RNA sequencing (bulk RNA-seq), we applied Cox regression models to compute hazard ratios, and cross-validated prognostic scoring using a GLMNET-based Cox model. Cell communication analysis was used to elucidate the potential mechanisms of CPVL and MSR1. Ultimately, RNA interference-mediated gene knockdown was utilized to validate the impact of specific genes on the polarization of tumor-associated macrophages (TAMs).
Our findings revealed that the function of immune cells is more pivotal in prognosis, with TAMs showing the strongest correlation with TNBC patient outcomes, compared with other immune cells. Additionally, we identified CPVL and MSR1 as critical prognostic genes within TAMs, with CPVL expression positively correlated with favorable outcomes and MSR1 expression associated with poorer prognosis. Mechanistically, CPVL may contribute to favorable prognosis by inhibiting the SPP1-CD44 ligand-receptor and promoting CXCL9-CXCR3, C3-C3AR1 ligand-receptor, through which TAMs interact with other cells such as monocytes, neutrophils, and T cells. Moreover, cytokines including IL-18, IFNγR1, CCL20, and CCL2, along with complement-related gene like TREM2 and complement component CFD, may participate in the process of CPVL or MSR1 regulating macrophage polarization. Furthermore, RT-PCR experiments confirmed that CPVL is positively associated with M1-like TAM polarization, while MSR1 is linked to M2-like TAM polarization. Finally, the prognostic significance of these two genes is also validated in HER2-positive breast cancer subtypes.
CPVL and MSR1 are potential biomarkers for macrophage-mediated TNBC prognosis, suggesting the therapeutic potential of macrophage targeting in TNBC.
三阴性乳腺癌（TNBC）是最具侵袭性的乳腺癌亚型，在所有亚型中预后最差。肿瘤微环境（TME）中不同细胞亚群对TNBC患者预后的影响尚待阐明。
利用单细胞RNA测序（scRNA-seq）结合批量RNA测序（bulk RNA-seq），我们应用Cox回归模型计算风险比，并使用基于GLMNET的Cox模型进行交叉验证的预后评分。细胞通讯分析用于阐明CPVL和MSR1的潜在机制。最终，利用RNA干扰介导的基因敲低来验证特定基因对肿瘤相关巨噬细胞（TAM）极化的影响。
我们的研究结果表明，免疫细胞的功能在预后中更为关键，与其他免疫细胞相比，TAM与TNBC患者的预后相关性最强。此外，我们确定CPVL和MSR1是TAM中的关键预后基因，CPVL表达与良好预后呈正相关，而MSR1表达与较差预后相关。从机制上讲，CPVL可能通过抑制SPP1-CD44配体-受体并促进CXCL9-CXCR3、C3-C3AR1配体-受体来促进良好预后，通过这些配体-受体TAM与单核细胞、中性粒细胞和T细胞等其他细胞相互作用。此外，包括IL-18、IFNγR1、CCL20和CCL2在内的细胞因子以及与补体相关的基因如TREM2和补体成分CFD，可能参与CPVL或MSR1调节巨噬细胞极化的过程。此外，RT-PCR实验证实CPVL与M1样TAM极化呈正相关，而MSR1与M2样TAM极化有关。最后，这两个基因在HER2阳性乳腺癌亚型中的预后意义也得到了验证。
CPVL和MSR1是巨噬细胞介导的TNBC预后的潜在生物标志物提示了TNBC中靶向巨噬细胞疗法的潜力
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