Adenovirus serotype 5 E1A sensitizes tumor cells to NKG2D-dependent NK cell lysis and tumor rejection.
The expression of the Adenovirus serotype 5 (Ad5) E1A oncogene sensitizes tumor cells to natural killer (NK) cell-mediated killing and tumor rejection in vivo. These effects are dependent on the ability of E1A to bind the transcriptional coadaptor protein p300. To test the hypothesis that E1A up-regulates ligands recognized by the NKG2D-activating receptor, we stably transfected the highly tumorigenic mouse fibrosarcoma cell line MCA-205 with Ad5-E1A or a mutant form of E1A that does not interact with p300 (E1A-Deltap300). Ad5-E1A, but not E1A-Deltap300, up-regulated the expression of the NKG2D ligand retinoic acid early inducible (RAE)-1, but not murine ULBP-like transcript 1, another NKG2D ligand, in four independently derived MCA-205 transfectants. The up-regulation of RAE-1 by E1A targeted MCA-205 tumor cells to lysis by NK cells, resulting in NKG2D-dependent tumor rejection in vivo. Moreover, the up-regulation of NKG2D ligands by E1A was not limited to mouse tumor cells, as E1A also increased the expression of NKG2D ligands on primary baby mouse kidney cells, human MB435S breast cancer cells, and human H4 fibrosarcoma cells.
Routes
John M
JM
Integrated Department of Immunology, National Jewish Medical and Research Center and the University of Colorado Health Sciences Center, Denver, CO 80262, USA. routesj@njc.org
Ryan
Sharon
S
Morris
Kristin
K
Takaki
Rayna
R
Cerwenka
Adelheid
A
Lanier
Lewis L
LL
D000256:Adenoviridae; D017500:Adenovirus E1A Proteins / Q000235:genetics / Q000276:immunology; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D045744:Cell Line, Tumor; D050881:E1A-Associated p300 Protein / Q000235:genetics / Q000276:immunology; D005354:Fibrosarcoma / Q000276:immunology*; D005822:Genetic Vectors; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology; D006801:Humans; D007668:Kidney / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D051379:Mice; D055655:NK Cell Lectin-Like Receptor Subfamily K; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000276:immunology; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000276:immunology; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology*; D055607:Receptors, Natural Killer Cell; D014212:Tretinoin / Q000008:administration & dosage; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
D017500:Adenovirus E1A Proteins; D000970:Antineoplastic Agents; C527085:KLRK1 protein, human; C527086:Klrk1 protein, mouse; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; D014212:Tretinoin; D050881:E1A-Associated p300 Protein; C494361:Ep300 protein, mouse