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Department of Animal Sciences, University of Missouri, Columbia, MO
2To whom correspondence should be addressed. E-mail: FritscheK{at}missouri.edu.
KEY WORDS: • eicosanoid • anti-inflammatory • IL-12
Evidence from epidemiological and animal experiments suggests that consumption of a diet rich in omega-3 fatty acids may diminish the incidence and/or severity of cancers of the prostate, breast, and colon (1–4). Several mechanisms have been proposed to explain the putative effect of these nutrients on cancer, including direct cytotoxic action on tumor cells, alteration of carcinogen metabolism, reduction in eicosanoid biosynthesis, alteration of gene expression, and improvement in one or more components of the host immune response against the tumor cells (5–7). Several different types of immune cells are thought to play a role in immunosurveillance [e.g., natural killer (NK), NKT, and 
T cells], while CD8+ T cells and cytolytic macrophages are central to immunotherapeutic treatment of existing tumors in cancer patients. The impact of omega-3 fatty acids on the immune system is generally characterized as anti-inflammatory (8). Reduced biosynthesis of various pro-inflammatory eicosanoids (e.g., prostaglandin E2 and leucotriene B4) and cytokines (e.g., TNF-
, IL-1ß, and IL-6) are well documented in humans and various animal models of cancer. Such changes may help explain the beneficial impact of omega-3 fatty acids on the tissue wasting and weight loss of cancer (i.e., cancer cachexia) (9). Elevated intake of omega-3 fatty acids is associated with reduced IL-12 and IFN- biosynthesis (10). These cytokines play a critical role in promoting Th1-type immune responses that are essential for the generation of cytolytic CD8+ T-cells and macrophages. That omega-3 fatty acids diminish in vivo host responsiveness to IFN- and diminish in vitro signal transducers and activators of transcription phosphorylation may undermine the usefulness of omega-3 fatty acids in adjunctive immunotherapy protocols (11). Furthermore, studies with animals, and a recent human supplementation study, suggest that omega-3 fatty acids may reduce basal NK cell activity (12–14). So it appears that alterations in various components of the immune system by omega-3 fatty acids may reduce host tumor immunity (15). However, little is known about the impact of these fatty acids on the function of NKT or T cells. Recent advances now make it possible to assess NK-cell activity in human blood samples, even though they only make up 
0.1% of the leukocytes present (16). In summary, it appears that whatever beneficial effects omega-3 fatty acids may have on cancer development or treatment, enhanced antitumor immunity is not playing a significant role in this activity.
Research needs
T cells in animals or humans. production during tumor development and immunotherapy should be conducted, since the existing data were collected in an infectious disease model.
FOOTNOTES
1 Published in a supplement to The Journal of Nutrition. Presented during a workshop entitled: "Immunonutrition: Enhancing Tumoricidal Cell Activity," held in Bethesda, MD, March 23, 2005. This workshop was sponsored by the Division of Cancer Prevention, NCI, NIH, DHHS. Guest editors for the supplement publication were Susan S. Percival, John A. Milner, and Christopher A. Jolly. Guest Editor Disclosure: Susan S. Percival: no relationships to disclose; John A. Milner: no relationships to disclose; Christopher A. Jolly: received reimbursement for travel expenses from NCI. 
LITERATURE CITED
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2. Gago-Dominguez M, Yuan JM, Sun CL, Lee, HP, Yu MC. Opposing effects of dietary n-3 and n-6 fatty acids on mammary carcinogenesis: The Singapore Chinese Health Study. Br J Cancer. 2003;89:1686-1692.[Medline]
3. Hardman WE. (n-3) fatty acids and cancer therapy. J Nutr. 2004;134:3427S-3430S.
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5. Wallace JM. Nutritional and botanical modulation of the inflammatory cascade–eicosanoids, cyclooxygenases, and lipoxygenases–as an adjunct in cancer therapy. Integr Cancer Ther. 2002;1:7-37.
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7. Terry PD, Terry JB, Rohan TE. Long-chain (n-3) fatty acid intake and risk of cancers of the breast and the prostate: recent epidemiological studies, biological mechanisms, and directions for future research. J Nutr. 2004;134:3412S-3420S.
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10. Fritsche KL, Anderson, M, Feng C. Consumption of eicosapentaenoic acid and docosahexaenoic acid impair murine interleukin-12 and interferon-gamma production in vivo. J Infect Dis. 2000;182(Suppl 1):S54-S61.
11. Irons R, Fritsche KL. Omega-3 polyunsaturated fatty acids impair in vivo interferon- gamma responsiveness via diminished receptor signaling. J Infect Dis. 2005;191:481-486.[Medline]
12. Purasiri P, McKechnie A, Heys SD, Eremin O. Modulation in vitro of human natural cytotoxicity, lymphocyte proliferative response to mitogens and cytokine production by essential fatty acids. Immunology. 1997;92:166-172.[Medline]
13. Almallah YZ, El-Tahir A, Heys SD, Richardson S, Eremin O. Distal procto-colitis and n-3 polyunsaturated fatty acids: the mechanism(s) of natural cytotoxicity inhibition. Eur J Clin Invest. 2000;30:58-65.[Medline]
14. Thies F, Nebe-von-Caron G, Powell JR, Yaqoob P, Newsholme EA, Calder PC. Dietary supplementation with eicosapentaenoic acid, but not with other long-chain n-3 or n-6 polyunsaturated fatty acids, decreases natural killer cell activity in healthy subjects aged >55 y. Am J Clin Nutr. 2001;73:539-458.
15. Salem ML, Kishihara K, Abe K, Matsuzaki G, Nomoto K. N-3 polyunsaturated fatty acids accentuate B16 melanoma growth and metastasis through suppression of tumoricidal function of T cells and macrophages. Anticancer Res. 2000;20:3195-203.[Medline]
16. Metelitsa LS. Flow cytometry for natural killer T cells: multi-parameter methods for multifunctional cells. Clin Immunol. 2004;110:267-276.[Medline]
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