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Cancer Immunology Research
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Research Articles

The Prognostic Role of Macrophage Polarization in the Colorectal Cancer Microenvironment

Juha P. Väyrynen, Koichiro Haruki, Mai Chan Lau, Sara A. Väyrynen, Rong Zhong, Andressa Dias Costa, Jennifer Borowsky, Melissa Zhao, Kenji Fujiyoshi, Kota Arima, Tyler S. Twombly, Junko Kishikawa, Simeng Gu, Saina Aminmozaffari, Shanshan Shi, Yoshifumi Baba, Naohiko Akimoto, Tomotaka Ugai, Annacarolina Da Silva, Jennifer L. Guerriero, Mingyang Song, Kana Wu, Andrew T. Chan, Reiko Nishihara, Charles S. Fuchs, Jeffrey A. Meyerhardt, Marios Giannakis, Shuji Ogino and Jonathan A. Nowak
Juha P. Väyrynen
1Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
2Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
3Cancer and Translational Medicine Research Unit, Medical Research Center Oulu, Oulu University Hospital, and University of Oulu, Oulu, Finland.
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  • ORCID record for Juha P. Väyrynen
Koichiro Haruki
2Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
4Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan.
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Mai Chan Lau
2Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
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Sara A. Väyrynen
1Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
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  • ORCID record for Sara A. Väyrynen
Rong Zhong
2Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
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Andressa Dias Costa
1Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
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Jennifer Borowsky
5Conjoint Gastroenterology Department, QIMR Berghofer Medical Research Institute, Queensland, Australia.
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Melissa Zhao
2Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
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Kenji Fujiyoshi
2Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
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  • ORCID record for Kenji Fujiyoshi
Kota Arima
2Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
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Tyler S. Twombly
2Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
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Junko Kishikawa
2Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
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Simeng Gu
2Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
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  • ORCID record for Simeng Gu
Saina Aminmozaffari
2Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
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  • ORCID record for Saina Aminmozaffari
Shanshan Shi
2Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
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Yoshifumi Baba
2Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
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Naohiko Akimoto
2Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
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Tomotaka Ugai
2Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
6Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
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Annacarolina Da Silva
2Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
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  • ORCID record for Annacarolina Da Silva
Jennifer L. Guerriero
7Breast Tumor Immunology Laboratory, Dana-Farber Cancer Institute, Boston, Massachusetts.
8Breast Oncology Program, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts.
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Mingyang Song
9Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
10Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
11Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts.
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Kana Wu
6Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
9Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
12Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
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Andrew T. Chan
10Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
11Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts.
12Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
13Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
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Reiko Nishihara
2Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
6Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
9Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
14Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
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Charles S. Fuchs
15Yale Cancer Center, New Haven, Connecticut.
16Department of Medicine, Yale School of Medicine, New Haven, Connecticut.
17Smilow Cancer Hospital, New Haven, Connecticut.
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Jeffrey A. Meyerhardt
1Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
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Marios Giannakis
1Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
18Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
19Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
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Shuji Ogino
2Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
6Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
18Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
20Cancer Immunology and Cancer Epidemiology Programs, Dana-Farber/Harvard Cancer Center, Boston, Massachusetts.
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  • For correspondence: janowak@bwh.harvard.edu sogino@bwh.harvard.edu
Jonathan A. Nowak
2Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
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  • For correspondence: janowak@bwh.harvard.edu sogino@bwh.harvard.edu
DOI: 10.1158/2326-6066.CIR-20-0527 Published January 2021
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Abstract

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.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/).

  • Cancer Immunol Res 2021;9:8–19

  • Received June 19, 2020.
  • Revision received August 13, 2020.
  • Accepted September 29, 2020.
  • Published first October 6, 2020.
  • ©2020 American Association for Cancer Research.
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Cancer Immunology Research: 9 (1)
January 2021
Volume 9, Issue 1
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The Prognostic Role of Macrophage Polarization in the Colorectal Cancer Microenvironment
Juha P. Väyrynen, Koichiro Haruki, Mai Chan Lau, Sara A. Väyrynen, Rong Zhong, Andressa Dias Costa, Jennifer Borowsky, Melissa Zhao, Kenji Fujiyoshi, Kota Arima, Tyler S. Twombly, Junko Kishikawa, Simeng Gu, Saina Aminmozaffari, Shanshan Shi, Yoshifumi Baba, Naohiko Akimoto, Tomotaka Ugai, Annacarolina Da Silva, Jennifer L. Guerriero, Mingyang Song, Kana Wu, Andrew T. Chan, Reiko Nishihara, Charles S. Fuchs, Jeffrey A. Meyerhardt, Marios Giannakis, Shuji Ogino and Jonathan A. Nowak
Cancer Immunol Res January 1 2021 (9) (1) 8-19; DOI: 10.1158/2326-6066.CIR-20-0527

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The Prognostic Role of Macrophage Polarization in the Colorectal Cancer Microenvironment
Juha P. Väyrynen, Koichiro Haruki, Mai Chan Lau, Sara A. Väyrynen, Rong Zhong, Andressa Dias Costa, Jennifer Borowsky, Melissa Zhao, Kenji Fujiyoshi, Kota Arima, Tyler S. Twombly, Junko Kishikawa, Simeng Gu, Saina Aminmozaffari, Shanshan Shi, Yoshifumi Baba, Naohiko Akimoto, Tomotaka Ugai, Annacarolina Da Silva, Jennifer L. Guerriero, Mingyang Song, Kana Wu, Andrew T. Chan, Reiko Nishihara, Charles S. Fuchs, Jeffrey A. Meyerhardt, Marios Giannakis, Shuji Ogino and Jonathan A. Nowak
Cancer Immunol Res January 1 2021 (9) (1) 8-19; DOI: 10.1158/2326-6066.CIR-20-0527
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