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Macrophage morphology correlates with single-cell diversity and prognosis in colorectal liver metastasis.

ABSTRACT: 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.

SUBMITTER: Donadon M

PROVIDER: S-EPMC7596819 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Macrophage morphology correlates with single-cell diversity and prognosis in colorectal liver metastasis.

Donadon Matteo M Torzilli Guido G Cortese Nina N Soldani Cristiana C Di Tommaso Luca L Franceschini Barbara B Carriero Roberta R Barbagallo Marialuisa M Rigamonti Alessandra A Anselmo Achille A Colombo Federico Simone FS Maggi Giulia G Lleo Ana A Cibella Javier J Peano Clelia C Kunderfranco Paolo P Roncalli Massimo M Mantovani Alberto A Marchesi Federica F

The Journal of experimental medicine 20201101 11

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 surviv ...[more]

PMID: 32785653

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Project description:IntroductionTumor-associated macrophages (TAMs) are key components of a tumoral microenvironment and have been shown to impact prognosis in different cancers. Previously reported data showed that TAM morphology correlates with prognosis in colorectal liver metastases (CLMs) after hepatectomy, with smaller TAMs (S-TAMs) conferring a more favorable prognosis than larger ones (L-TAMs). This study aims to externally validate this finding.Material and methodsThe external cohort consisted of 84 formalin-fixed and paraffin-embedded surgical samples of CLMs and peritumoral tissue. Two-micrometer-section slides were obtained; the area and perimeter of 21 macrophages in each slide were recorded. The endpoints were TAMs morphometrics and their prognostic significance in relation to disease-free survival (DFS).ResultsThe average macrophage perimeter was 71.5±14.1 μm whilst the average area was 217.7±67.8 μm 2 . At univariate analysis, the TAM area demonstrated a statistically significant association with DFS ( P =0.0006). Optimal area cutoff value was obtained, showing a sensitivity and specificity of 92 and 56%, respectively. S-TAMs and L-TAMs were associated with 3-year DFS rates of 60 and 8.5%, respectively ( P <0.001). Multivariate analysis confirmed the predictive role of TAM area for DFS [hazard ratio (HR)=5.03; 95% CI=1.70-14.94; P =0.003]. Moreover, in a subset of patients ( n =12) characterized by unfavorable ( n =6, recurrence within 3 months) or favorable ( n =6, no recurrence after 48 months) prognosis, TAMs showed a different distribution: L-TAMs were more abundant and closer to the tumor invasive margin in patients that encountered early recurrence and tended to cluster in foci significantly larger ( P =0.02).ConclusionsThis external validation confirms that morphometric characterization of TAMs can serve as a simple readout of their diversity and allows to reliably stratify patient outcomes and predict disease recurrence after hepatectomy for CLMs.

Project description:BackgroundLiver metastasis is the leading cause of death in colorectal cancer (CRC) patients, and the precise mechanisms remain unclear. In this study, single-cell RNA sequencing (scRNA-seq) was used to analyze the cellular and molecular heterogeneity between CRC primary lesion and corresponding liver metastasis, and to clarify the characteristics of the tumor microenvironment (TME) in synchronous liver metastasis of CRC.MethodsA case of microsatellite stable (MSS) sigmoid carcinoma with synchronous liver metastasis was selected, and tissues from the primary tumor and the liver metastasis were collected for scRNA-seq. The EdgeR package software was used to identify the differentially expressed genes between cells. Gene Set Enrichment Analysis (GSEA) was performed and the clusterProfiler R package was used for Gene Ontology (GO) enrichment analysis. The SCENIC and CellphoneDB packages were used to reconstruct the transcriptional regulatory networks and to analyze the intercellular interaction network, respectively.ResultsCompared to the primary tumor, the proportion of myeloid cells in the metastatic tumor was significantly increased, while B cells and plasma cells were decreased. In the metastatic tumor, the myeloid-derived suppressor cell (MDSC) characteristic gene, mannose receptor C-type 1 (MRC1) and tumor associated macrophage 2 (TAM2)-related gene, were highly expressed. Furthermore, angiogenesis, oxidative phosphorylation, and endothelial mesenchymal transition (EMT) of myeloid cells were also significantly enhanced. There were less myeloid cells in primary tumors, and these were mainly monocytes and TAM1; while the number of TAM2 was significantly upregulated in the metastatic samples. In liver metastasis, the T cell population was exhausted, and this was accompanied by a significant increase in the number of CD4+ T cells and a decrease in the number of CD8+ T cells. Furthermore, some immune checkpoint molecules were highly expressed. Interactions between myeloid cells and other cell populations appeared to be strong.ConclusionsThe TME of CRC liver metastasis is significantly immunosuppressed. Interactions between myeloid cells and other cell populations in the TME contribute to the establishment of a pro-metastatic niche that promotes colonization and growth of CRC cells in the liver. TAMs may be a potential immunotherapeutic target for MSS CRC.

Dataset Information

Macrophage morphology correlates with single-cell diversity and prognosis in colorectal liver metastasis.

Publications

Macrophage morphology correlates with single-cell diversity and prognosis in colorectal liver metastasis.

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