The Journal of Experimental Medicine
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Published online 28 November 2005 doi:10.1084/jem.20050240
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 202, Number 11, 1477-1482
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ARTICLE

 Adenovirus serotype 5 E1A sensitizes tumor cells to NKG2D-dependent NK cell lysis and tumor rejection

John M. Routes1,2,3, Sharon Ryan1, Kristin Morris1, Rayna Takaki4, Adelheid Cerwenka4, and Lewis L. Lanier4

1 Integrated Department of Immunology, National Jewish Medical and Research Center and the University of Colorado Health Sciences Center, Denver, CO 80262
2 Department of Medicine, National Jewish Medical and Research Center and the University of Colorado Health Sciences Center, Denver, CO 80262
3 Cancer Center, National Jewish Medical and Research Center and the University of Colorado Health Sciences Center, Denver, CO 80262
4 Department of Microbiology and Immunology, Biomedical Sciences Graduate Program, and the Cancer Research Institute, University of California, San Francisco, San Francisco, CA 94143

CORRESPONDENCE John M. Routes: routesj{at}njc.org

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-{Delta}p300). Ad5-E1A, but not E1A-{Delta}p300, 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.

Abbreviations used: Ad, adenovirus; BMK, baby mouse kidney; HPV, human papillomavirus; MULT1, murine ULBP-like transcript 1; RAE, retinoic acid early inducible; Rb, retinoblastoma.

A. Cerwenka's present address is Deutsches Krebsforschungszentrum, DKFZ, 69120 Heidelberg, Germany.


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