title: Marine ω-3 Polyunsaturated Fatty Acid Intake and Risk of Colorectal Cancer Characterized by Tumor-Infiltrating T Cells.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  This prospective cohort study was conducted among participants in the Nurses' Health Study (1984-2010) and Health Professionals Follow-up Study (1986-2010).
  
  
  METHODS
  Intake of marine ω-3 PUFAs.
  
  
  METHODS
  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
  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.
authors.affiliation: 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.
authors.forename: Mingyang
authors.initials: M
authors.lastname: Song
authors.affiliation: 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.
authors.forename: Reiko
authors.initials: R
authors.lastname: Nishihara
authors.affiliation: 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.
authors.forename: Yin
authors.initials: Y
authors.lastname: Cao
authors.affiliation: 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.
authors.forename: Eunyoung
authors.initials: E
authors.lastname: Chun
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
authors.forename: Zhi Rong
authors.initials: ZR
authors.lastname: Qian
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Mima
authors.affiliation: Division of Pathology, Cancer Institute, Japanese Foundation For Cancer Research, Tokyo, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Inamura
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Masugi
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Nowak
authors.affiliation: Department of Gastroenterology, Rheumatology, and Clinical Immunology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Nosho
authors.affiliation: Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
authors.forename: Kana
authors.initials: K
authors.lastname: Wu
authors.affiliation: 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.
authors.forename: Molin
authors.initials: M
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Edward
authors.initials: E
authors.lastname: Giovannucci
authors.affiliation: 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.
authors.forename: Wendy S
authors.initials: WS
authors.lastname: Garrett
authors.affiliation: 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.
authors.forename: Charles S
authors.initials: CS
authors.lastname: Fuchs
authors.affiliation: 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.
authors.forename: Shuji
authors.initials: S
authors.lastname: Ogino
authors.affiliation: 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.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Chan
mesh_terms: D000328:Adult; D000368:Aged; D017252:CD3 Complex / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000453:epidemiology* / Q000276:immunology; D004032:Diet / Q000706:statistics & numerical data*; D015525:Fatty Acids, Omega-3; D005260:Female; D005500:Follow-Up Studies; D051858:Forkhead Transcription Factors / Q000276:immunology; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D015994:Incidence; D017493:Leukocyte Common Antigens / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D011446:Prospective Studies; D065840:Protective Factors; D017747:Seafood; D014481:United States / Q000453:epidemiology
chemical_list: D017252:CD3 Complex; C418974:FOXP3 protein, human; D015525:Fatty Acids, Omega-3; D051858:Forkhead Transcription Factors; D017493:Leukocyte Common Antigens; C516769:PTPRC protein, human