University of Oulu

Väyrynen, J. P., Haruki, K., Lau, M. C., Väyrynen, S. A., Zhong, R., Dias Costa, A., Borowsky, J., Zhao, M., Fujiyoshi, K., Arima, K., Twombly, T. S., Kishikawa, J., Gu, S., Aminmozaffari, S., Shi, S., Baba, Y., Akimoto, N., Ugai, T., Da Silva, A., … Nowak, J. A. (2020). The Prognostic Role of Macrophage Polarization in the Colorectal Cancer Microenvironment. Cancer Immunology Research, 9(1), 8–19.

The prognostic role of macrophage polarization in the colorectal cancer microenvironment

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Author: Väyrynen, Juha P.1,2,3; Haruki, Koichiro2,4; Lau, Mai Chan2;
Organizations: 1Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA
2Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
3Cancer and Translational Medicine Research Unit, Medical Research Center Oulu, Oulu University Hospital, and University of Oulu, Oulu, Finland
4Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan
5Conjoint Gastroenterology Department, QIMR Berghofer Medical Research Institute, Queensland, Australia
6Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA
7Breast Tumor Immunology Laboratory, Dana-Farber Cancer Institute, Boston, MA
8Breast Oncology Program, Dana- Farber/Brigham and Women’s Cancer Center, Boston, MA
9Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA
10Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA
11Division of Gastroenterology, Massachusetts General Hospital, Boston, MA
12Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
13Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA
14Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston
15Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA
16Yale Cancer Center, New Haven, CT
17Department of Medicine, Yale School of Medicine, New Haven, CT
18Smilow Cancer Hospital, New Haven, CT
19Broad Institute of MIT and Harvard, Cambridge, MA
20Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA;
21Cancer Immunology and Cancer Epidemiology Programs, Dana-Farber Harvard Cancer Center, Boston, MA
Format: article
Version: accepted version
Access: open
Online Access: PDF Full Text (PDF, 1.6 MB)
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Language: English
Published: American Association for Cancer Research, 2021
Publish Date: 2021-10-06


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.

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Series: Cancer immunology research
ISSN: 2326-6066
ISSN-E: 2326-6074
ISSN-L: 2326-6066
Volume: 9
Issue: 1
Pages: 8 - 19
DOI: 10.1158/2326-6066.CIR-20-0527
Type of Publication: A1 Journal article – refereed
Field of Science: 3122 Cancers
Funding: This work was supported by NIH grants (P01 CA87969 to M.J. Stampfer; UM1 CA186107 to M.J. Stampfer; P01 CA55075 to W.C. Willett; UM1 CA167552 to W.C. Willett; U01 CA167552 to W.C. Willett and L.A. Mucci; P50 CA127003 to C.S. Fuchs; R01 CA118553 to C.S. Fuchs; R01 CA169141 to C.S. Fuchs; R01 CA137178 to A.T. Chan; K24 DK098311 to A.T. Chan; R35 CA197735 to S. Ogino; R01 CA151993 to S. Ogino; K07 CA190673 to R. Nishihara; R03 CA197879 to K. Wu; R21 CA222940 to K. Wu and M. Giannakis; and R21 CA230873 to K. Wu and S. Ogino); by the Cancer Research UK Grand Challenge Award (UK C10674/A27140 to M. Giannakis and S. Ogino); by the Nodal Award (2016–02) from the Dana-Farber Harvard Cancer Center (to S. Ogino); by grants from the Project P Fund, The Friends of the Dana-Farber Cancer Institute, the Bennett Family Fund, and the Entertainment Industry Foundation through the National Colorectal Cancer Research Alliance; and by the Stand Up To Cancer Colorectal Cancer Dream Team Translational Research Grant (SU2C-AACR-DT22-17 to C.S. Fuchs and M. Giannakis). Stand Up To Cancer is a division of the Entertainment Industry Foundation. The SU2C research grant is administered by the American Association for Cancer Research, a scientific partner of SU2C. K. Haruki was supported by fellowship grants from the Uehara Memorial Foundation and the Mitsukoshi Health and Welfare Foundation. S.A. Väyrynen was supported by grants from the Finnish Cultural Foundation and Orion Research Foundation sr. J. Borowsky was supported by a grant from the Australia Awards-Endeavour Scholarships and Fellowships Program. K. Fujiyoshi was supported by a fellowship grant from the Uehara Memorial Foundation. K. Arima was supported by grants from Overseas Research Fellowship from Japan Society for the Promotion of Science (JP201860083). K. Wu was supported by an Investigator Initiated Grant from the American Institute for Cancer Research (AICR). A.T. Chan is a Stuart and Suzanne Steele MGH Research Scholar. J.A. Meyerhardt's research is supported by the Douglas Gray Woodruff Chair fund, the Guo Shu Shi Fund, the Anonymous Family Fund for Innovations in Colorectal Cancer, the Project P fund, and the George Stone Family Foundation. M. Giannakis was supported by a Conquer Cancer Foundation of ASCO Career Development Award.
Dataset Reference: Supplementary data for this article are available at Cancer Immunology Research Online (
Copyright information: © 2020 American Association for Cancer Research.