The Prognostic Role of Macrophage Polarization in the Colorectal Cancer Microenvironment.
The Prognostic Role of Macrophage Polarization in the Colorectal Cancer Microenvironment.
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DOI：
10.1158/2326-6066.cir-20-0527
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发表时间：
2021-01
影响因子：
10.1
通讯作者：
Nowak JA
中科院分区：
文献类型：
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作者：
Väyrynen JP;Haruki K;Lau MC;Väyrynen SA;Zhong R;Dias Costa A;Borowsky J;Zhao M;Fujiyoshi K;Arima K;Twombly TS;Kishikawa J;Gu S;Aminmozaffari S;Shi S;Baba Y;Akimoto N;Ugai T;Da Silva A;Guerriero JL;Song M;Wu K;Chan AT;Nishihara R;Fuchs CS;Meyerhardt JA;Giannakis M;Ogino S;Nowak JA
巨噬细胞是结直肠癌微环境中最常见的细胞之一，但其预后意义尚不完全清楚。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，我们评估了931例结直肠癌中肿瘤相关巨噬细胞的偏振光谱。然后，我们应用考克斯比例风险回归来评估M1样和M2样巨噬细胞的上皮内和间质密度与预后生存的关系，同时控制潜在的混杂因素，包括分期和微卫星不稳定状态。我们发现M2样巨噬细胞的高肿瘤基质密度与更差的癌症特异性生存相关，而M1样巨噬细胞的肿瘤基质密度与更好的癌症特异性生存无显著相关性。肿瘤间质中高M1：M2密度比与更好的癌症特异性生存相关。肿瘤上皮内或间质区域的总体巨噬细胞密度不是预后性的。这些发现表明，巨噬细胞的极化状态，而不是它们的整体密度，与癌症特异性生存相关，M1和M2样巨噬细胞表型表现出不同的预后作用。这些结果突出了多标记策略在肿瘤微环境内以单细胞分辨率评估巨噬细胞极化的效用。
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.