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

J Natl Cancer Inst

BACKGROUND: 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.

METHODS: 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.

RESULTS: 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).

CONCLUSIONS: 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.

Year of Publication
J Natl Cancer Inst
Date Published
2019 Jan 01
PubMed ID
PubMed Central ID
Grant list
R35 CA197735 / CA / NCI NIH HHS / United States
R01 CA118553 / CA / NCI NIH HHS / United States
P01 CA087969 / CA / NCI NIH HHS / United States
P30 DK043351 / DK / NIDDK NIH HHS / United States
UM1 CA186107 / CA / NCI NIH HHS / United States
T32 CA009001 / CA / NCI NIH HHS / United States
R00 CA215314 / CA / NCI NIH HHS / United States
U01 CA167552 / CA / NCI NIH HHS / United States
L30 CA209764 / CA / NCI NIH HHS / United States