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J Natl Cancer Inst. 2019 Jan 1;111(1):42-51. doi: 10.1093/jnci/djy137.

Smoking and Risk of Colorectal Cancer Sub-Classified by Tumor-Infiltrating T Cells.

Hamada T1, Nowak JA2,3, Masugi Y1, Drew DA4, Song M4,5, Cao Y4,5,6, Kosumi K1, Mima K2, Twombly TS1, Liu L1,5,6,7, Shi Y1,8, da Silva A1, Gu M1,9, Li W1, Nosho K10, Keum N5,11, Giannakis M2,12,13, Meyerhardt JA, Wu K14,5,15, Wang M14,15,16, Chan AT14,4, Giovannucci EL14,5,15, Fuchs CS17,18,19, Nishihara R1,3,5,15,16, Zhang X14, Ogino S1,3,15,13.

Author information

Department of Oncologic Pathology.
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA.
Program in Molecular Pathological Epidemiology, Department of Pathology.
Clinical and Translational Epidemiology Unit, and Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA.
Department of Nutrition.
Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, MO.
Department of Epidemiology and Biostatistics, and the Ministry of Education Key Lab of Environment and Health, School of Public Health, Huazhong University of Science and Technology, Hubei, P.R. China.
Department of Medical Oncology, Chinese PLA General Hospital, Beijing, P.R. China.
College of Pharmacy, Zhejiang Chinese Medical University, Zhejiang, P.R. China.
Department of Gastroenterology, Rheumatology, and Clinical Immunology, Sapporo Medical University School of Medicine, Sapporo, Japan.
Department of Food Science and Biotechnology, Dongguk University, Goyang, the Republic of Korea.
Department of Medicine, and Channing Division of Network Medicine.
Broad Institute of MIT and Harvard, Cambridge, MA.
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
Department of Epidemiology.
Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA.
Yale Cancer Center, New Haven, CT.
Department of Medicine, Yale School of Medicine, New Haven, CT.
Smilow Cancer Hospital, New Haven, CT.

Erratum in



Evidence indicates not only carcinogenic effect of cigarette smoking but also its immunosuppressive effect. We hypothesized that the association of smoking with colorectal cancer risk might be stronger for tumors with lower anti-tumor adaptive immune response.


During follow-up of 134 981 participants (3 490 851 person-years) in the Nurses' Health Study and Health Professionals Follow-up Study, we documented 729 rectal and colon cancer cases with available data on T-cell densities in tumor microenvironment. Using the duplication-method Cox regression model, we examined a differential association of smoking status with risk of colorectal carcinoma subclassified by densities of CD3+ cells, CD8+ cells, CD45RO (PTPRC)+ cells, or FOXP3+ cells. All statistical tests were two-sided.


The association of smoking status with colorectal cancer risk differed by CD3+ cell density (Pheterogeneity = .007). Compared with never smokers, multivariable-adjusted hazard ratios for CD3+ cell-low colorectal cancer were 1.38 (95% confidence interval = 1.09 to 1.75) in former smokers and 1.59 (95% confidence interval = 1.14 to 2.23) in current smokers (Ptrend = .002, across smoking status categories). In contrast, smoking status was not associated with CD3+ cell-high cancer risk (Ptrend = .52). This differential association appeared consistent in strata of microsatellite instability, CpG island methylator phenotype, or BRAF mutation status. There was no statistically significant differential association according to densities of CD8+ cells, CD45RO+ cells, or FOXP3+ cells (Pheterogeneity > .04, with adjusted α of 0.01).


Colorectal cancer risk increased by smoking was stronger for tumors with lower T-lymphocyte response, suggesting an interplay of smoking and immunity in colorectal carcinogenesis.

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