NKG2D function protects the host from tumor initiation.
The activation NKG2D receptor has been shown to play an important role in the control of experimental tumor growth and metastases expressing ligands for NKG2D; however, a function for this recognition pathway in host protection from de novo tumorigenesis has never been demonstrated. We show that neutralization of NKG2D enhances the sensitivity of wild-type (WT) C57BL/6 and BALB/c mice to methylcholanthrene (MCA)-induced fibrosarcoma. The importance of the NKG2D pathway was additionally illustrated in mice deficient for either IFN-gamma or tumor necrosis factor-related apoptosis-inducing ligand, whereas mice depleted of natural killer cells, T cells, or deficient for perforin did not display any detectable NKG2D phenotype. Furthermore, IL-12 therapy preventing MCA-induced sarcoma formation was also largely dependent on the NKG2D pathway. Although NKG2D ligand expression was variable or absent on sarcomas emerging in WT mice, sarcomas derived from perforin-deficient mice were Rae-1(+) and immunogenic when transferred into WT syngeneic mice. These findings suggest an important early role for the NKG2D in controlling and shaping tumor formation.
Smyth
Mark J
MJ
Cancer Immunology Program, Trescowthick Laboratories, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. mark.smyth@petermac.org
Swann
Jeremy
J
Cretney
Erika
E
Zerafa
Nadeen
N
Yokoyama
Wayne M
WM
Hayakawa
Yoshihiro
Y
D000818:Animals; D000911:Antibodies, Monoclonal; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency; D002352:Carrier Proteins / Q000378:metabolism; D005354:Fibrosarcoma / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism*; D005434:Flow Cytometry; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism / Q000627:therapeutic use; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000172:deficiency; D008565:Membrane Proteins; D008748:Methylcholanthrene; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D055655:NK Cell Lectin-Like Receptor Subfamily K; D009500:Neutralization Tests; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D011971:Receptors, Immunologic / Q000378:metabolism*; D055607:Receptors, Natural Killer Cell; D015398:Signal Transduction / Q000276:immunology*
D000911:Antibodies, Monoclonal; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D015395:Histocompatibility Antigens Class I; C527086:Klrk1 protein, mouse; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D055655:NK Cell Lectin-Like Receptor Subfamily K; D052899:Pore Forming Cytotoxic Proteins; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; C468260:UL16 binding protein 1, mouse; D054353:Perforin; D018664:Interleukin-12; D008748:Methylcholanthrene