Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
Cancer Immunol Res. 2021 Jan;9(1):8-19. doi: 10.1158/2326-6066.CIR-20-0527. Epub 2020 Oct 6.
Macrophages are among the most common cells in the colorectal cancer microenvironment, but their prognostic significance is incompletely understood. Using multiplexed immunofluorescence for CD68, CD86, IRF5, MAF, MRC1 (CD206), and KRT (cytokeratins) combined with digital image analysis and machine learning, we assessed the polarization spectrum of tumor-associated macrophages in 931 colorectal carcinomas. We then applied Cox proportional hazards regression to assess prognostic survival associations of intraepithelial and stromal densities of M1-like and M2-like macrophages while controlling for potential confounders, including stage and microsatellite instability status. We found that high tumor stromal density of M2-like macrophages was associated with worse cancer-specific survival, whereas tumor stromal density of M1-like macrophages was not significantly associated with better cancer-specific survival. High M1:M2 density ratio in tumor stroma was associated with better cancer-specific survival. Overall macrophage densities in tumor intraepithelial or stromal regions were not prognostic. These findings suggested that macrophage polarization state, rather than their overall density, was associated with cancer-specific survival, with M1- and M2-like macrophage phenotypes exhibiting distinct prognostic roles. These results highlight the utility of a multimarker strategy to assess the macrophage polarization at single-cell resolution within the tumor microenvironment.
巨噬细胞是结直肠癌微环境中最常见的细胞之一，但它们的预后意义尚不完全清楚。我们使用 CD68、CD86、IRF5、MAF、MRC1（CD206）和 KRT（细胞角蛋白）的多重免疫荧光，结合数字图像分析和机器学习，评估了 931 例结直肠癌中肿瘤相关巨噬细胞的极化谱。然后，我们应用 Cox 比例风险回归来评估上皮内和基质内 M1 样和 M2 样巨噬细胞密度与潜在混杂因素（包括分期和微卫星不稳定性状态）的预后生存关联。我们发现，肿瘤基质中 M2 样巨噬细胞的高密度与癌症特异性生存不良相关，而 M1 样巨噬细胞的肿瘤基质密度与癌症特异性生存改善无显著相关性。肿瘤基质中 M1:M2 密度比与癌症特异性生存相关。肿瘤上皮内或基质区域的总巨噬细胞密度与预后无关。这些发现表明，巨噬细胞极化状态而非其总体密度与癌症特异性生存相关，M1 样和 M2 样巨噬细胞表型表现出不同的预后作用。这些结果突出了使用多标志物策略在肿瘤微环境中单细胞分辨率评估巨噬细胞极化的实用性。
