Hamada T, et al. – Given that cigarette smoking has immunosuppressive effects in addition to carcinogenic effects, researchers investigated whether the association of smoking with colorectal cancer risk might be stronger for tumors with lower anti-tumor adaptive immune response. Outcomes indicated a stronger increase in colorectal cancer risk by smoking for tumors with lower T-lymphocyte response, suggesting an interplay of smoking and immunity in colorectal carcinogenesis.

Methods

• Researchers documented 729 rectal and colon cancer cases with available data on T-cell densities in tumor microenvironment during follow-up of 134,981 participants (3,490,851 person-years) in the Nurses’ Health Study and Health Professionals Follow-up Study.
• 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 was examined using the duplication-method Cox regression model.
• Two-sided statistical tests were conducted.

Results

• CD3+cell density influenced the association between smoking status and colorectal cancer risk (P_{heterogeneity}=0.007).
• Compared with never-smokers, multivariable-adjusted hazard ratios for CD3+ cell-low colorectal cancer were 1.38 (95% CI: 1.09-1.75) and 1.59 (95% CI: 1.14-2.23) in former smokers and current smokers, respectively (P_trend=0.002, across smoking status categories).
• In contrast, they did not observe any association of smoking status with CD3+ cell-high cancer risk (P_trend=0.52).
• In strata of microsatellite instability, CpG island methylator phenotype, or BRAF mutation status, the differential association seemed consistent.
• No statistically significant differential association was noted in accordance to densities of CD8+ cells, CD45RO+ cells, or FOXP3+ cells (P_{heterogeneity} > 0.04, with adjusted α of 0.01).