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Tumor Immunity within the Central Nervous System Stimulated by Recombinant Listeria monocytogenes Vaccination¹

Division of Neurosurgery [L. M. L., T. J. K., S. K. O., S. N. S., M. C. S.], Department of Microbiology, Immunology, & Molecular Genetics [E. R. J., J. F. M.], Department of Neurology [J. M. B.], the Molecular Biology Institute [J. F. M.], the Brain Research Institute [L. M. L., J. M. B.], and the Jonsson Comprehensive Cancer Center [L. M. L., J. F. M.], University of California at Los Angeles School of Medicine, Los Angeles, California 90095

Tumors arising within the central nervous system (CNS) present the immunesystem with a challenging target, given the heterogeneous nature ofthese neoplasms and their location within an "immunologicaly privileged" site. We used the lymphocytic choriomeningitis virus nucleoprotein (LCMV-NP) as a pseudotumor antigen to investigate recombinant Listeria monocytogenes as a tumor vaccine against s.c. and intracerebral challenges with a NP-expressing glioma, 9L-NP. Using Fischer 344 rats, we demonstrate that vaccination with recombinant L. monocytogenes-NP stimulates protection against s.c., but not intracerebral, 9L-NP tumor challenge in an antigen-specific, CD8⁺ T-cell-dependent manner. After s.c. tumor rejection, enhanced antitumor immunity is achieved via epitope spreading that permits complete resistance against lethal intracerebral challenge with 9L-NP and with the untransfected parental 9L tumor. Unlike the CD8⁺-dependent immune responses against s.c. 9L-NP tumors, this expanded intracerebral immunity against endogenous tumor-associated antigens is dependent on both CD4⁺ and CD8⁺ T cells. Taken together, these results demonstrate that the mechanisms of tumor immunity within the brain are different from those elicited against non-CNS tumors. Furthermore, vaccination approaches exploiting the concept of epitope spreading may enhance the efficacy of antitumor immune responses within the immunologically privileged CNS, potentially mediating tumor cell killing through both CD4⁺- and CD8⁺-dependent effector pathways.

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