Tomotaka Ugai1,2, Juha P Väyrynen1,3,4, Koichiro Haruki1, Naohiko Akimoto1, Mai Chan Lau1, Rong Zhong1,2, Junko Kishikawa1, Sara A Väyrynen3, Melissa Zhao1, Kenji Fujiyoshi1, Andressa Dias Costa1, Jennifer Borowsky5, Kota Arima1, Jennifer L Guerriero6,7, Charles S Fuchs8,9,10,11, Xuehong Zhang12,13, Mingyang Song12,14,15, Molin Wang2,13,16, Marios Giannakis3,17,18, Jeffrey A Meyerhardt3, Jonathan A Nowak1, Shuji Ogino1,2,17,19. 1. Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA. 2. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA. 3. Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. 4. Cancer and Translational Medicine Research Unit, Medical Research Center Oulu, Oulu University Hospital, and University of Oulu, Oulu, Finland. 5. Conjoint Gastroenterology Department, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. 6. Breast Tumor Immunology Laboratory, Dana-Farber Cancer Institute, Boston, MA, USA. 7. Division of Breast Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, MA, USA. 8. Yale Cancer Center, New Haven, CT, USA. 9. Department of Medicine, Yale School of Medicine, New Haven, CT, USA. 10. Smilow Cancer Hospital, New Haven, CT, USA. 11. Genentech, South San Francisco, CA, USA. 12. Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA. 13. Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. 14. Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. 15. Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA. 16. Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA. 17. Broad Institute of MIT and Harvard, Cambridge, MA, USA. 18. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. 19. Cancer Immunology and Cancer Epidemiology Programs, Dana-Farber Harvard Cancer Center, Boston, MA, USA.
Abstract
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 = .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 = .004). In contrast, pack-years smoked was not statistically significantly associated with the incidence of tumors having intermediate or high macrophage densities (Ptrend > .009, with an α level of .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.
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 = .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 = .004). In contrast, pack-years smoked was not statistically significantly associated with the incidence of tumors having intermediate or high macrophage densities (Ptrend > .009, with an α level of .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.
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