Natural cytotoxicity receptors include now three molecules specific for unknown host ligands: NKp46, NKp30, and NKp44 (8, 9), which mediate cell lysis of many cancer cells. Additional surface molecules have been implicated in NK cell activation and tumor cell lysis; these include 2B4, NTB-A, NKp80 coreceptors, CD18/CD11 (ß2 integrins), CD2 adhesion molecules, and TLR (8, 9, 12, 16, 17). In particular, viral and bacterial products can trigger NK cell responses directly binding to surface TLR3 and TLR9 (16, 17). More in general, NK cells can be activated by various stimuli such as contact with dendritic cells (DC), MHC-I-negative cells, binding of IgG immunocomplexes, direct engagement of NKR by stress-induced tumor-associated molecules or pathogen-derived products, and several cytokines such as IL-1, IL-2, IL-12, IL-15, IL-18, IL-21, and type I IFNs (8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25). Upon cytokine stimulation, NK cells become lymphokine-activated killer.
Jpn J Cancer Res. 1994;85(12):1288-1297. 24. Yamasaki K, Sone S, Yamashita T, Ogura T. Synergistic induction of lymphokine (IL-2)-activated killer activity by IL-2 and the polysaccharide lentinan, and therapy of spontaneous pulmonary metastases. Cancer Immunol Immunother. 1989;29(2):87-92. 25. Yang P, Liang M, Zhang Y, Shen B. Clinical application of a combination therapy of lentinan, multi-electrode RFA and TACE in HCC.
Triggering resting NK cells to kill occurs through integration of activating and inhibitory receptor signals, which is referred to as natural killing . Stimulation with IL-2 or IL-15 for several days results in lymphokine-activated killer (LAK) cells, which have the capacity to kill additional targets that are resistant to resting blood NK cells . For human NK cells, CD16 (the FcγRIIIa receptor) is a major activating receptor that recognizes antibody-coated target cells, and killing through this activation mode is referred to as antibody-dependent cellular cytotoxicity (ADCC) .
Cancer,*Surgical resident under Dr. Jakowatz's direction. 12. Carson WE*, Jakowatz JG, Yamamoto RS, Fitzgerald T, Gupta S, Vayuvegula B, Lucci JA, Beckman MT, Dulkanchainun SB, Granger GA, and Jeffes EWB. Rat mitogen-stimulated lymphokine activated (MAK) T killer cells: Production and effects on C6 glioma cells in vitro and in vivo in the brain of Wistar rats. Journal of Immunotherapy 10:131-140, 1990.
Rosenberg, S. A. et al. Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N. Engl. J. Med. 313, 1485–1492 (1985).