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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2019.01875

The two faces of tumor-associated macrophages and their clinical significance in colorectal cancer

 Marta L. Pinto1, 2, 3, Elisabete Rios1, 4, 5, 6,  Cecília Durães1, 4,  Ricardo Ribeiro1, 2, 7, 8,  José C. Machado1, 4, 5,  Alberto Mantovani9, 10, Mário A. Barbosa1, 2, 3,  Fatima M. Carneiro1, 4, 5, 6 and  Maria J. Oliveira1, 5, 11*
  • 1Institute of Research and Innovation in Health, University of Porto, Portugal
  • 2National Institute of Biomedical Engineering, Faculty of Engineering, University of Porto, Portugal
  • 3Abel Salazar Institute of Biomedical Sciences, University of Porto, Portugal
  • 4Institute of Pathology and Molecular Immunology, Abel Salazar Institute of Biomedical Sciences, University of Porto, Portugal
  • 5Department of Pathology, Faculty of Medicine, University of Porto, Portugal
  • 6Centro Hospitalar São João, Portugal
  • 7Laboratory of Genetics & Environmental Health Institute, Faculty of Medicine, University of Lisbon, Portugal
  • 8Department of Clinical Pathology, Hospital and University Center of Coimbra, Portugal
  • 9Humanitas Clinical and Research Center, Milan University, Italy
  • 10Humanitas University, Italy
  • 11Microenvironments for Newtherapies, National Institute of Biomedical Engineering, Faculty of Engineering, University of Porto, Portugal

Macrophages are the most prevalent immune population in colorectal cancer (CRC) and high macrophage infiltration has been associated with both better and worst prognosis. Importantly, according to microenvironment stimuli, macrophages may adopt different polarization profiles, specifically the pro-inflammatory or M1 and the anti-inflammatory or M2, which display distinct functions. Therefore, concomitantly with the number of tumor-associated macrophages (TAMs), their characterization is fundamental to unravel their relevance in cancer. Here, we profiled macrophages in a series of 150 CRC cases by immunohistochemistry, using CD68 as a macrophage lineage marker, CD80 as a marker of pro-inflammatory macrophages, and CD163 as a marker of anti-inflammatory macrophages. Quantifications were performed by computer-assisted analysis in the intratumoral region, tumor invasive front and matched tumor adjacent normal mucosa. Macrophages, specifically the CD163+ ones, were predominantly found at the tumor invasive front, whereas CD80+ macrophages were almost exclusively located in the adjacent normal mucosa, which suggests a predominant anti-inflammatory polarization of TAMs. Stratification according to tumor stage revealed that macrophages, specifically the CD163+ ones, are more prevalent in stage II tumors, whereas CD80+ macrophages are predominant in less invasive T1 tumors. Specifically in stage III tumors, higher CD68 and lower CD80/CD163 ratio associated with decreased overall survival. Importantly, despite the low infiltration of CD80+ cells in colorectal tumors, multivariate logistic regression revealed a protective role of these cells regarding the risk for relapse. Overall, this work highlights how the distinct microenvironments, present at the intratumor, invasive front and adjacent normal mucosa regions, modulate the different macrophage subpopulations, and uncovers their prognostic value, further supporting the relevance of including macrophage profiling in clinical settings.

Keywords: colorectal cancer, tumor immunomodulation, Tumor-associated macrophages, human macrophage surface markers, Macrophage polarization, tumor prognostic and relapse

Received: 23 May 2019; Accepted: 24 Jul 2019.

Edited by:

Kate E. Lawlor, Hudson Institute of Medical Research, Australia

Reviewed by:

Tracy Putoczki, Walter and Eliza Hall Institute of Medical Research, Australia
Una Riekstina, University of Latvia, Latvia  

Copyright: © 2019 Pinto, Rios, Durães, Ribeiro, Machado, Mantovani, Barbosa, Carneiro and Oliveira. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Maria J. Oliveira, Institute of Research and Innovation in Health, University of Porto, Porto, Portugal, mariajo@ineb.up.pt