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Supplement: Immunonutrition: Enhancing Tumoricidal Cell Activity

Biology of Natural Killer Cells: What Is the Relationship between Natural Killer Cells and Cancer? Will an Increased Number and/or Function of Natural Killer Cells Result in Lower Cancer Incidence?¹

Science Applications International Corporation-Frederick, Inc., Frederick, MD

²To whom correspondence should be addressed. E-mail: andersn{at}ncifcrf.gov.

KEY WORDS: • natural killer cell • Ly49 • KIR

Natural killer (NK) cells are bone marrow derived lymphocytes originally identified by their large granular morphology and their ability to spontaneously lyse certain tumor targets in vivo and in vitro without prior sensitization (1). NK cells are also able to eliminate metastatic cells in the circulation. The adverse effects of uncontrolled or inappropriate NK cell responses are evident in pathological conditions such as allograft rejection, graft vs. host disease, diabetes, various autoimmune and neurological diseases, and aplastic anemia/neutropenia. The importance of normal NK cell function in the immune system is best demonstrated in reports of individuals lacking NK cells and/or NK-cell-like activity. One such patient was constantly afflicted with viral infections, including severe chicken pox and vermicelli pneumonia, and eventually developed critical human cytomegalovirus and herpes simplex virus infections (2). In addition, papilla viral infections and the resulting recurrent cervical carcinoma have also been linked with the absence of NK cells in another patient (3). Collectively, these observations show that NK cells are a vital component of the immune response that constantly protects an individual from life-threatening infections.

NK-cells are also important mediators of antitumor immunity. This is clearly displayed in transgenic mice with severely decreased levels of NK cells. Such mice have decreased resistance to B16 experimental lung metastases and RMA tumor outgrowth. Furthermore, protection from the development of carcinogen-induced tumors is dependent on NK cells.

NK cells use a large number of receptors to identify potential target cells. The highly polymorphic nature of NK cell receptors for Class I molecules (KIR or Ly49) may provide a genetic explanation for why some mouse strains or human individuals are resistant or susceptible to various diseases.

NK-cell responses toward tumor cells are controlled in part by expression of receptors for ligands often expressed on tumor cells such as the MIC/Rae1 stress-induced molecules recognized by the NKG 2D surface receptor. Also, the frequently observed reduction of class I major histocompatibility complex (MHC) expression on tumors confers susceptibility to NK cell lysis. Normal class Ia and Ib MHC expression is thought to result in NK-cell tolerance through inhibitory class I MHC receptors such as KIR, Ly49, and NKG2A. Finally, analogous to HIV infection, patients with cancer have decreased NK function as measured by cytotoxicity, production of cytokines, and proliferation.

NK cells mediate their protective effect in 2 ways: cytotoxicity and cytokine production. Cytotoxicity in NK cells (and cytotoxic T lymphocytes) is carried out by granule exocytosis of membrane pore-forming molecules (perforin) and proteases (granzymes) or death ligand interactions (FasL and TRAIL). Upon target-cell binding, NK cells will also produce large amounts of cytokines, such as interferon (IFN) g, TNF, and granulocyte-macrophage colony-stimulating factor. Natural and induced mutations of cytokine (IFN-g and IL-2/IL-15Rb) and cytotoxicity-associated genes (perforin, granzyme A and B, FasL) that are expressed by NK cells also negatively affect antiviral responses and the rejection of tumors (4–6).

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

1. Trinchieri G. Biology of natural killer cells. Adv Immunol. 1989;47:187-376.[Medline]

2. Biron CA, Byron KS, Sullivan JL. Severe herpes virus infections in an adolescent without natural killer cells. N Engl J Med. 1989;320:1731-1735.[Medline]

3. Ballas ZK, Turner JM, Turner DA, Goetzman EA, Kemp JD. A patient with simultaneous absence of "classical" natural killer cells (CD3-, CD16+, and NKH1+) and expansion of CD3+, CD4-, CD8-, NKH1+ subset. J Allergy Clin Immunol. 1990;85:453-459.[Medline]

4. van den Broek MF, Kagi D, Zinkernagel RM, Hengartner H. Perforin dependence of natural killer cell-mediated tumor control in vivo. Eur J Immunol. 1995;25:3514-3516.[Medline]

5. Takeda K, Hayakawa Y, Smyth MJ, Kayagaki N, Yamaguchi N, Kakuta S, Iwakura Y, Yagita H, Okumura K. Involvement of tumor necrosis factor-related apoptosis-inducing ligand in surveillance of tumor metastasis by liver natural killer cells. Nat Med. 2001;7:94-100.[Medline]

6. Smyth MJ, Cretney E, Takeda K, Wiltrout RH, Sedger LM, Kayagaki N, Yagita H, Okumura K. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) contributes to interferon gamma-dependent natural killer cell protection from tumor metastasis. J Exp Med. 2001;193:661-670.[Abstract/Free Full Text]

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