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

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.
Competing Interests: Disclosures: A. Mantovani reported personal fees from Ventana, Pierre Fabre, Verily, AbbVie, Astra Zeneca, Verseau Therapeutics, Compugen, Myeloid Therapeutics, Third Rock Venture, Imcheck Therapeutics, Ellipses, Novartis, Roche, Macrophage Pharma, Biovelocita, Merck, and Principia; grants from Novartis; and "other" from Cedarlane Laboratories Ltd, Hycult Biotechnology, eBioscience, BioLegend, ABCAM Plc, Novus Biologicals, Enzo Life (ex-Alexis Corp.), and Affymetrix outside the submitted work. He is the inventor of patents related to PTX3 and other innate immunity molecules and receives royalties for reagents related to innate immunity. No other disclosures were reported.
(© 2020 Donadon et al.)