University of Oulu

Ugai, T., Väyrynen, J. P., Haruki, K., Akimoto, N., Lau, M. C., Zhong, R., Kishikawa, J., Väyrynen, S. A., Zhao, M., Fujiyoshi, K., Dias Costa, A., Borowsky, J., Arima, K., Guerriero, J. L., Fuchs, C. S., Zhang, X., Song, M., Wang, M., Giannakis, M., … Ogino, S. (2022). Smoking and incidence of colorectal cancer subclassified by tumor-associated macrophage infiltrates. JNCI: Journal of the National Cancer Institute, 114(1), 68–77.

Smoking and incidence of colorectal cancer subclassified by tumor-associated macrophage infiltrates

Saved in:
Author: Ugai, Tomotaka1,2; Väyrynen, Juha P.1,3,4; Haruki, Koichiro1;
Organizations: 1Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA, USA
2Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
3Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
4Cancer and Translational Medicine Research Unit, Medical Research Center Oulu, Oulu University Hospital, and University of Oulu, Oulu, Finland
5Conjoint Gastroenterology Department, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
6Breast Tumor Immunology Laboratory, Dana-Farber Cancer Institute, Boston, MA, USA;
7Division of Breast Surgery, Department of Surgery, Brigham and Women’s Hospital, Boston, MA, USA
8Yale Cancer Center, New Haven, CT, USA
9Department of Medicine, Yale School of Medicine, New Haven, CT, USA
10Smilow Cancer Hospital, New Haven, CT, USA
11Genentech, South San Francisco, CA, USA
12Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA
13Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
14Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
15Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA
16Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA
17Broad Institute of MIT and Harvard, Cambridge, MA, USA
18Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
19Cancer Immunology and Cancer Epidemiology Programs, Dana-Farber Harvard Cancer Center, Boston, MA, USA
Format: article
Version: accepted version
Access: open
Online Access: PDF Full Text (PDF, 1.3 MB)
Persistent link:
Language: English
Published: Oxford University Press, 2022
Publish Date: 2022-07-15


Background: Biological evidence indicates that smoking can influence macrophage functions and polarization, thereby promoting tumor evolution. We hypothesized that the association of smoking with colorectal cancer incidence might differ by macrophage infiltrates.

Methods: Using the Nurses’ Health Study and the Health Professionals Follow-up Study, we examined the association of smoking with incidence of colorectal cancer subclassified by macrophage counts. Multiplexed immunofluorescence (for CD68, CD86, IRF5, MAF, and MRC1 [CD206]) combined with digital image analysis and machine learning was used to identify overall, M1‐polarized, and M2‐polarized macrophages in tumor. We used inverse-probability–weighted multivariable Cox proportional hazards regression models to control for potential confounders and selection bias because of tissue data availability. All statistical tests were 2-sided.

Results: During follow-up of 131 144 participants (3 648 370 person-years), we documented 3092 incident colorectal cancer cases, including 871 cases with available macrophage data. The association of pack-years smoked with colorectal cancer incidence differed by stromal macrophage densities (Pheterogeneity = 0.003). Compared with never smoking, multivariable-adjusted hazard ratios (95% confidence interval) for tumors with low macrophage densities were 1.32 (0.97 to 1.79) for 1–19 pack-years, 1.31 (0.92 to 1.85) for 20–39 pack-years, and 1.74 (1.26 to 2.41) for 40 or more pack-years (Ptrend = 0.004). In contrast, pack-years smoked was not statistically significantly associated with the incidence of tumors having intermediate or high macrophage densities (Ptrend > 0.009, with an α level of 0.005). No statistically significant differential association was found for colorectal cancer subclassified by M1‐like or M2‐like macrophages.

Conclusions: The association of smoking with colorectal cancer incidence is stronger for tumors with lower stromal macrophage counts. Our findings suggest an interplay of smoking and macrophages in colorectal carcinogenesis.

see all

Series: JNCI. Journal of the National Cancer Institute
ISSN: 0027-8874
ISSN-E: 1460-2105
ISSN-L: 0027-8874
Volume: 114
Issue: 1
Pages: 68 - 77
DOI: 10.1093/jnci/djab142
Type of Publication: A1 Journal article – refereed
Field of Science: 3122 Cancers
Funding: This work was supported by U.S. National Institutes of Health (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.F.; R01 CA118553 to C.S.F.; R01 CA169141 to C.S.F.; R01 CA137178 to A.T.C.; K24 DK098311 to A.T.C.; R35 CA197735 to S.O.; R01 CA151993 to S.O.; R01 CA248857 to S.O., U. Peters, and A.I. Phipps; R00 CA215314 to M.S.; and K07 CA188126 to X.Z.); by Nodal Award (2016–02) from the Dana-Farber Harvard Cancer Center (to S.O.); by the Stand Up to Cancer Colorectal Cancer Dream Team Translational Research Grant (SU2C-AACR-DT22-17 to C.S.F. and M.G.), administered by the American Association for Cancer Research, a scientific partner of SU2C; by the American Cancer Society Mentored Research Scholar Grant (MRSG-17–220-01 - NEC to M.S.); and by grants from the Project P Fund, The Friends of the Dana-Farber Cancer Institute, Bennett Family Fund, and the Entertainment Industry Foundation through National Colorectal Cancer Research Alliance. T.U., K.H., and K.F. were supported by fellowship grants from the Uehara Memorial Foundation. K.H. was supported by the Mitsukoshi Health and Welfare Foundation. T.U. was supported by Yasuda Medical Foundation. S.A.V. was supported by grants from the Finnish Cultural Foundation and Orion Research Foundation sr. J.B. was supported by a grant from the Australia Awards-Endeavour Scholarships and Fellowships Program. K.A. and T.U. were supported by a grant from Overseas Research Fellowship (201860083 to K.A.; 201960541 to T.U.) from Japan Society for the Promotion of Science. M.G. was supported by a Conquer Cancer Foundation of ASCO Career Development Award. J.A.M. research is supported by the Douglas Gray Woodruff Chair fund, the Guo Shu Shi Fund, Anonymous Family Fund for Innovations in Colorectal Cancer, Project P fund, and the George Stone Family Foundation.
Copyright information: © The Author(s) 2021. Published by Oxford University Press. All rights reserved. This is a pre-copyedited, author-produced version of an article accepted for publication in Journal of the National Cancer Institute following peer review. The version of record Tomotaka Ugai, MD, PhD, Juha P Väyrynen, MD, PhD, Koichiro Haruki, MD, PhD, Naohiko Akimoto, MD, PhD, Mai Chan Lau, PhD, Rong Zhong, PhD, Junko Kishikawa, MD, PhD, Sara A Väyrynen, MD, PhD, Melissa Zhao, MD, MS, Kenji Fujiyoshi, MD, PhD, Andressa Dias Costa, MD, Jennifer Borowsky, MBChB, Kota Arima, MD, PhD, Jennifer L Guerriero, PhD, Charles S Fuchs, MD, MPH, Xuehong Zhang, MD, ScD, Mingyang Song, MD, ScD, Molin Wang, PhD, Marios Giannakis, MD, PhD, Jeffrey A Meyerhardt, MD, MPH, Jonathan A Nowak, MD, PhD, Shuji Ogino, MD, PhD, MS, Smoking and Incidence of Colorectal Cancer Subclassified by Tumor-Associated Macrophage Infiltrates, JNCI: Journal of the National Cancer Institute, 2022; 114(1), 68–77 is available online at: