Background: Several tumor-associated macrophages (TAMs) have shown promise as prognosticators in cancer. Our aim was to validate the importance of TAMs in malignant pleural mesothelioma (MPM) using a two-stage design. Methods: We explored The Cancer Genome Atlas (TCGA-MESO) to select immune-relevant macrophage genes in MPM, including M1/M2 markers, as a discovery cohort. This computational cohort was used to create a multiplex immunofluorescence panel. Moreover, a cohort of 68 samples of MPM in paraffin blocks was used to validate the macrophage phenotypes and the co-localization and spatial distribution of these immune cells within the TME and the stromal or tumor compartments. Results: The discovery cohort revealed six immune-relevant macrophage genes (CD68,CD86,CD163,CD206,ARG1,CD274), and complementary genes were differentially expressed by M1 and M2 phenotypes with distinct roles in the tumor microenvironment and were associated with the prognosis. In addition, immune-suppressed MPMs with increased enrichment of CD68, CD86, and CD163 genes and high densities of M2 macrophages expressing CD163 and CD206 proteins were associated with worse overall survival (OS). Interestingly, below-median distances from malignant cells to specific M2a and M2c macrophages were associated with worse OS, suggesting an M2 macrophage-driven suppressive component in these tumors. Conclusions: The interactions between TAMs in situ and, particularly, CD206+macrophages are highly relevant to patient outcomes. High-resolution technology is important for identifying the roles of macrophage populations in tissue specimens and identifying potential therapeutic candidates in MPM.
背景：多种肿瘤相关巨噬细胞（TAMs）已显示出作为癌症预后指标的潜力。本研究旨在通过两阶段设计验证TAMs在恶性胸膜间皮瘤（MPM）中的重要性。方法：我们利用癌症基因组图谱（TCGA-MESO）数据库作为发现队列，筛选MPM中与免疫相关的巨噬细胞基因（包括M1/M2标记物），并据此构建多重免疫荧光检测组合。同时，采用68例石蜡包埋的MPM样本队列，用于验证巨噬细胞表型及其在肿瘤微环境、间质或肿瘤区域内的共定位与空间分布特征。结果：发现队列筛选出六个免疫相关巨噬细胞基因（CD68、CD86、CD163、CD206、ARG1、CD274），这些基因在M1与M2表型中呈现差异表达，在肿瘤微环境中发挥不同作用且与预后相关。此外，CD68、CD86、CD163基因富集度升高且表达CD163与CD206蛋白的M2巨噬细胞密度较高的免疫抑制型MPM，其总生存期（OS）更差。值得注意的是，恶性细胞与特定M2a、M2c巨噬细胞的距离低于中位数与较差的OS相关，提示这些肿瘤中存在M2巨噬细胞驱动的抑制性成分。结论：原位TAMs（尤其是CD206+巨噬细胞）的相互作用与患者预后密切相关。高分辨率技术对于解析组织样本中巨噬细胞亚群的作用及识别MPM潜在治疗靶点具有重要意义。
肿瘤(癌症)患者之家