Department of Hepatobiliary and General Surgery, Humanitas Clinical and Research Center - IRCCS, Rozzano, Italy.
Department of Biomedical Science, Humanitas University, Rozzano, Italy.
J Exp Med. 2020 Nov 2;217(11). doi: 10.1084/jem.20191847.
It has long been known that in vitro polarized macrophages differ in morphology. Stemming from a conventional immunohistology observation, we set out to test the hypothesis that morphology of tumor-associated macrophages (TAMs) in colorectal liver metastasis (CLM) represents a correlate of functional diversity with prognostic significance. Density and morphological metrics of TAMs were measured and correlated with clinicopathological variables. While density of TAMs did not correlate with survival of CLM patients, the cell area identified small (S-TAM) and large (L-TAM) macrophages that were associated with 5-yr disease-free survival rates of 27.8% and 0.2%, respectively (P < 0.0001). RNA sequencing of morphologically distinct macrophages identified LXR/RXR as the most enriched pathway in large macrophages, with up-regulation of genes involved in cholesterol metabolism, scavenger receptors, MERTK, and complement. In single-cell analysis of mononuclear phagocytes from CLM tissues, S-TAM and L-TAM signatures were differentially enriched in individual clusters. These results suggest that morphometric characterization can serve as a simple readout of TAM diversity with strong prognostic significance.
长期以来，人们已经知道体外极化的巨噬细胞在形态上存在差异。基于传统免疫组织化学观察，我们开始测试这样一个假设，即结直肠癌肝转移（CLM）中肿瘤相关巨噬细胞（TAMs）的形态代表了与功能多样性相关的预后意义的指标。我们测量了 TAMs 的密度和形态学指标，并将其与临床病理变量相关联。虽然 TAMs 的密度与 CLM 患者的生存无关，但细胞面积确定了小（S-TAM）和大（L-TAM）巨噬细胞，它们与 5 年无病生存率分别为 27.8%和 0.2%（P < 0.0001）相关。对形态不同的巨噬细胞进行 RNA 测序，发现 LXR/RXR 是大巨噬细胞中最丰富的途径，上调了参与胆固醇代谢、清道夫受体、MERTK 和补体的基因。在 CLM 组织单核吞噬细胞的单细胞分析中，S-TAM 和 L-TAM 特征在单个簇中差异富集。这些结果表明，形态特征可以作为 TAM 多样性的简单读出，具有很强的预后意义。
