Importance: Marine ω-3 polyunsaturated fatty acids possess potent immunomodulatory activity and may protect against cancer development. However, evidence relating marine ω-3 polyunsaturated fatty acids to colorectal cancer risk remains inconclusive.

Objective: To test the hypothesis that marine ω-3 polyunsaturated fatty acid intake may be associated with lower risk of colorectal cancer subsets characterized by immune infiltrate.

Design: Prospective cohort study

Setting: Nurses’ Health Study and Health Professionals Follow-up Study

Participants: In the two cohorts, 125,172 participants provided data about marine ω-3 polyunsaturated fatty acid intake every 4 years through a validated food frequency questionnaire and followed up for incident colorectal cancer over 24-26 years. We documented 614 colorectal cancer cases from which we could assess T-cell infiltration in the tumor microenvironment. Cause-specific Cox proportional hazards regression was used to estimate hazard ratios and 95% confidence intervals for risks of colorectal cancer subtypes.

Exposure: Intake of marine ω-3 polyunsaturated fatty acids

Main Outcome and Measures: Incidence of colorectal cancer according to tumor-infiltrating T cells

Results: The inverse association of marine ω-3 polyunsaturated fatty acids with colorectal cancer risk differed according to FOXP3+ T-cell infiltration (P for heterogeneity = 0.006). Compared to intake of <0.15 g/day of marine ω-3 PUFAs, intake of ≥0.35 g/day was associated with a multivariable hazard ratio of 0.57 (95% confidence interval, 0.40 to 0.81) (P for trend < 0.001) for FOXP3+ T-cell-high tumors. In contrast, the corresponding hazard ratio was 1.14 (95% confidence interval, 0.81 to 1.60) (P for trend = 0.77) for FOXP3+ T-cell-low tumors. No statistically significant differential association was found according to tumor-infiltrating CD3+, CD8+, or CD45RO+ T cells (P for heterogeneity ≥ 0.34). In functional assays, the suppressive activity of regulatory T cells was approximately two-fold lower when pre-incubated with marine ω-3 polyunsaturated fatty acids at 50, 100 and 200 μM than without marine ω-3 polyunsaturated fatty acids (P<0.0001).

Conclusion and Relevance: High marine ω-3 polyunsaturated fatty acid intake was associated with lower risk of colorectal cancer with high-level, but not low-level, FOXP3+ T-cell density, suggesting a potential role of ω-3 polyunsaturated fatty acids in cancer immunoprevention through modulation of regulatory T cells.

Citation Format: Mingyang Song, Reiko Nishihara, Yin Cao, Eunyoung Chun, Zhi Rong Qian, Kosuke Mima, Kentaro Inamura, Yohei Masugi, Jonathan Nowak, Katsuhiko Nosho, Kana Wu, Molin Wang, Edward Giovannucci, Wendy S. Garrett, Charles S. Fuchs, Shuji Ogino, Andrew T. Chan. Marine ω-3 polyunsaturated fatty acid intake and risk of colorectal cancer according to tumor-infiltrating T cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1418.