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* Department of Surgery, Division of Neurosurgery,
Department of Microbiology, Immunology and Molecular Genetics,
Department of Surgery, Division of Surgical Oncology,
Jonsson Comprehensive Cancer Center, and
¶ Department of Medicine, Division of Hematology-Oncology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095
NK cells represent a potent immune effector cell type that have the ability to recognize and lyse tumors. However, the existence and function of NK cells in the traditionally "immune-privileged" CNS is controversial. Furthermore, the cellular interactions involved in NK cell anti-CNS tumor immunity are even less well understood. We administered non-Ag-loaded, immature dendritic cells (DC) to CD8
knockout (KO) mice and studied their anti-CNS tumor immune responses. DC administration induced dramatic antitumor immune protection in CD8 KO mice that were challenged with B16 melanoma both s.c. and in the brain. The CNS antitumor immunity was dependent on both CD4+ T cells and NK cells. Administration of non-Ag-loaded, immature DC resulted in significant CD4+ T cell and NK cell expansion in the draining lymph nodes at 6 days postvaccination, which persisted for 2 wk. Finally, DC administration in CD8 KO mice was associated with robust infiltration of CD4+ T cells and NK cells into the brain tumor parenchyma. These results represent the first demonstration of a potent innate antitumor immune response against CNS tumors in the absence of toxicity. Thus, non-Ag-loaded, immature DC administration, in the setting of CD8 genetically deficient mice, can induce dramatic antitumor immune responses within the CNS that surpass the effects observed in wild-type mice. Our results suggest that a better understanding of the cross-talk between DC and innate immune cells may provide improved methods to vaccinate patients with tumors located both systemically and within the CNS.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by Grant R01 CA 79976 from the National Cancer Institute (NCI), National Institutes of Health (to J.S.E.) and Project 1 Grant P50 CA086306 from the University of California, Los Angeles, Center for In Vivo Imaging in Cancer Biology (to A.R.), and by the Philip R. and Kenneth A. Jonsson Foundation (to L.M.L.), the Musella Foundation for Brain Tumor Research (to L.M.L. and R.M.P.), the Neidorf Foundation (to L.M.L. and R.M.P.), and the Monkarsh Fund (to J.S.E.). R.M.P. was supported by an NCI Cancer Education Grant R25 CA 098010 and a NCI, National Institutes of Health Grant K01 CA111402. A.R. is a recipient of a STOP CANCER Career Development Award and Grant K23 CA93376.
2 Address correspondence and reprint requests to Dr. Robert M. Prins, Division of Neurosurgery, Center for Health Sciences 74-145, University of California, P.O. Box 956901, 10833 Le Conte Avenue, Los Angeles, CA 90095. E-mail address: rprins{at}mednet.ucla.edu
3 Abbreviations used in this paper: TAA, tumor-associated Ag; DC, dendritic cell; BLI, bioluminescent imaging; CD62L, L-selectin; i.c., intracranial; KO, knockout.
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