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

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

Author information

1
Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston2Division of Gastroenterology, Massachusetts General Hospital, Boston3Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
2
Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts4Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts5Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts6Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
3
Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, Massachusetts8Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.
4
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
5
Division of Pathology, Cancer Institute, Japanese Foundation For Cancer Research, Tokyo, Japan.
6
Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
7
Department of Gastroenterology, Rheumatology, and Clinical Immunology, Sapporo Medical University School of Medicine, Sapporo, Japan.
8
Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
9
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts6Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
10
Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts5Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts12Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
11
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts7Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, Massachusetts8Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, Massachusetts13Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge.
12
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts12Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
13
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts5Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts10Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
14
Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston2Division of Gastroenterology, Massachusetts General Hospital, Boston12Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts13Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge.

Abstract

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.

PMID:
27148825
PMCID:
PMC5016204
DOI:
10.1001/jamaoncol.2016.0605
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Disclosures: Andrew T. Chan previously served as a consultant for Bayer Healthcare, Pozen Inc, and Pfizer Inc. for work unrelated to the topic of this manuscript. This study was not funded by Bayer Healthcare, Pozen Inc, or Pfizer Inc. No other conflict of interest exists.

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