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Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
Novel anticancer vaccination regimens that can elicit large numbers of Ag-specific T cells are needed. When we administered therapeutic vaccines containing the MHC class I-presented self-peptide tyrosinase-related protein (TRP)-2180–188 and CpG-containing oligodeoxynucleotides (CpG ODN) to mice, growth of the TRP-2-expressing B16F1 melanoma was not inhibited compared with growth in mice that received control vaccinations. When we added systemic IL-2 to the TRP-2180–188 plus CpG ODN vaccines, growth of B16F1 was inhibited in a CD8-dependent, epitope-specific manner. Vaccines containing TRP-2180–188 without CpG ODN did not cause epitope-specific tumor growth inhibition when administered with IL-2. The antitumor efficacy of the different regimens correlated with their ability to elicit TRP-2180–188-specific CD8+ T cell responses. When we administered TRP-2180–188 plus CpG ODN-containing vaccines with systemic IL-2, 18.2% of CD8+ T cells were specific for TRP-2180–188. Identical TRP-2180–188 plus CpG ODN vaccines given without IL-2 elicited a TRP-2180–188-specific CD8+ T cell response of only 1.1% of CD8+ T cells. Vaccines containing TRP-2180–188 without CpG ODN elicited TRP-2180–188-specific responses of 2.8% of CD8+ T cells when administered with IL-2. There was up to a 221-fold increase in the absolute number of TRP-2180–188-specific CD8+ T cells when IL-2 was added to TRP-2180–188 plus CpG ODN-containing vaccines. Peptide plus CpG ODN vaccines administered with IL-2 generated epitope-specific CD8+ T cells by a mechanism that depended on endogenous IL-6. This is the first report of synergism between CpG ODN and IL-2. This synergism caused a striking increase in vaccine-elicited CD8+ T cells and led to epitope-specific antitumor immunity.
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 by intramural funding of the National Cancer Institute.
2 Address correspondence and reprint requests to Dr. James N. Kochenderfer, National Institutes of Health, 10 Center Drive, Clinical Research Center 3-3288, Bethesda, MD 20892. E-mail address: kochendj{at}mail.nih.gov
3 Abbreviations used in this paper: ODN, oligodeoxynucleotide; Treg, T regulatory cell; TRP, tyrosine-related protein; CPP, cell-penetrating peptide; HBC, hepatitis B core; RSV, respiratory syncytial virus; ICCS, intracellular cytokine staining; 7-AAD, 7-aminoactinomycin D.
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