ULBPs, human ligands of the NKG2D receptor, stimulate tumor immunity with enhancement by IL-15.
ULBPs are human ligands for NKG2D, an activating receptor expressed on natural killer (NK) cells, NK1.1(+) T cells, and T cells. ULBPs are expressed by a variety of leukemias, carcinomas, melanomas, and tumor cell lines. ULBP expression correlates with improved survival in cancer patients, however, the nature of the immune response that ULBPs elicit is not well understood. We report that ectopic expression of ULBP1 or ULBP2 on murine EL4 or RMA tumor cells elicits potent antitumor responses in syngeneic C57BL/6 and SCID mice. Although binding of ULBP3 to murine NKG2D could not be demonstrated in vitro, ULBP3 can also stimulate antitumor responses, suggesting that ULBP3 binds to murine NKG2D or possibly another receptor in vivo. ULBP expression was found to recruit NK cells, NK1.1(+) T cells, and T cells to the tumor. IL-15 was found to strongly enhance the immune response directed against ULBP-expressing tumors. Tumors can evade NKG2D immunity by down-regulating expression of NKG2D. Our data suggest that IL-15 may be useful for overcoming this tumor-evasion strategy. Together, these results demonstrate that ULBP expression can elicit a potent immune response and suggest that ULBPs, alone or in combination with IL-15, can be exploited for antitumor therapy.
Sutherland
Claire L
CL
Department of Oncology, Amgen Inc, Seattle, WA, 98119, USA. sutherlc@amgen.com
Rabinovich
Brian
B
Chalupny
N Jan
NJ
Brawand
Pierre
P
Miller
Robert
R
Cosman
David
D
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D058851:GPI-Linked Proteins; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D019409:Interleukin-15 / Q000276:immunology*; D047908:Intracellular Signaling Peptides and Proteins; D007694:Killer Cells, Natural / Q000276:immunology; D008024:Ligands; D008565:Membrane Proteins; D051379:Mice; D016513:Mice, SCID; D055655:NK Cell Lectin-Like Receptor Subfamily K; D009363:Neoplasm Proteins / Q000276:immunology*; D009369:Neoplasms / Q000235:genetics / Q000276:immunology* / Q000401:mortality / Q000628:therapy; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology*; D055607:Receptors, Natural Killer Cell; D013601:T-Lymphocytes / Q000276:immunology; D019139:Tumor Escape / Q000235:genetics / Q000276:immunology
D002352:Carrier Proteins; D058851:GPI-Linked Proteins; D015395:Histocompatibility Antigens Class I; D036341:Intercellular Signaling Peptides and Proteins; D019409:Interleukin-15; D047908:Intracellular Signaling Peptides and Proteins; C527085:KLRK1 protein, human; C527086:Klrk1 protein, mouse; D008024:Ligands; D008565:Membrane Proteins; D055655:NK Cell Lectin-Like Receptor Subfamily K; D009363:Neoplasm Proteins; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; C423231:ULBP1 protein, human; C423230:ULBP2 protein, human; C423229:ULBP3 protein, human