Marine ω-3 Polyunsaturated Fatty Acid Intake and Risk of Colorectal Cancer Characterized by Tumor-Infiltrating T Cells

JAMA Oncol. 2016 Sep 1;2(9):1197-206. doi: 10.1001/jamaoncol.2016.0605.


Importance: Marine ω-3 polyunsaturated fatty acids (PUFAs), including eicosapentaenoic acid, docosahexaenoic acid, and docosapentaenoic acid, possess potent immunomodulatory activity and may protect against cancer development. However, evidence relating marine ω-3 PUFAs to colorectal cancer (CRC) risk remains inconclusive.

Objective: To test the hypothesis that marine ω-3 PUFA intake may be associated with lower risk of CRC subsets characterized by immune infiltrate.

Design, setting, and participants: This prospective cohort study was conducted among participants in the Nurses' Health Study (1984-2010) and Health Professionals Follow-up Study (1986-2010).

Exposures: Intake of marine ω-3 PUFAs.

Main outcomes and measures: Incidence of CRC characterized by CD3+, CD8+, CD45RO (PTPRC)+, or FOXP3+ T-cell densities in tumor tissue, measured by immunohistochemical and computer-assisted image analysis.

Results: Among 173 229 predominantly white participants, 125 172 with 2 895 704 person-years of follow-up provided data about marine ω-3 PUFA intake every 4 years through a validated food frequency questionnaire and followed up for incident CRC evaluation. Of 2504 CRC cases, we documented 614 (252 men, 362 women) from which we could assess T-cell infiltration in the tumor microenvironment. The inverse association of marine ω-3 PUFAs intake with CRC risk differed according to FOXP3+ T-cell infiltration: compared with intake of less than 0.15 g/d of marine ω-3 PUFAs, intake of at least 0.35 g/d was associated with a multivariable hazard ratio (HR) of 0.57 (95% CI, 0.40-0.81; P < .001 for trend) for FOXP3+ T-cell-high tumors. In contrast, the HR for FOXP3+ T-cell-low tumors was 1.14 (95% CI, 0.8-1.60) (P = .77 for trend; P = .01 for heterogeneity). No statistically significant differential association was found for high-density tumors (compared with low-density tumors) according to CD3+, CD8+, or CD45RO+ cell density (P ≥ .34 for heterogeneity for all comparisons). In functional assays, the suppressive activity of regulatory T cells was approximately 2-fold lower (T-effector-cell proliferation, ≥64% vs 38%) when preincubated with docosahexaenoic acid at 50μM, 100μM, and 200μM concentrations than without docosahexaenoic acid (P < .001 for all comparisons).

Conclusions and relevance: High marine ω-3 PUFA intake was associated with lower risk of CRC with high-level, but not low-level, FOXP3+ T-cell density, suggesting a potential role of ω-3 PUFAs in cancer immunoprevention through modulation of regulatory T cells.

MeSH terms

  • Adult
  • Aged
  • CD3 Complex / immunology
  • CD8-Positive T-Lymphocytes / immunology*
  • Cohort Studies
  • Colorectal Neoplasms / epidemiology*
  • Colorectal Neoplasms / immunology
  • Diet / statistics & numerical data*
  • Fatty Acids, Omega-3*
  • Female
  • Follow-Up Studies
  • Forkhead Transcription Factors / immunology
  • Humans
  • Image Processing, Computer-Assisted
  • Immunohistochemistry
  • Incidence
  • Leukocyte Common Antigens / immunology
  • Lymphocytes, Tumor-Infiltrating / immunology*
  • Male
  • Middle Aged
  • Proportional Hazards Models
  • Prospective Studies
  • Protective Factors
  • Seafood*
  • United States / epidemiology


  • CD3 Complex
  • FOXP3 protein, human
  • Fatty Acids, Omega-3
  • Forkhead Transcription Factors
  • Leukocyte Common Antigens
  • PTPRC protein, human