Synergism between CpG-containing oligodeoxynucleotides and IL-2 causes dramatic enhancement of vaccine-elicited CD8+ T cell responses.
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)-2(180-188) 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-2(180-188) plus CpG ODN vaccines, growth of B16F1 was inhibited in a CD8-dependent, epitope-specific manner. Vaccines containing TRP-2(180-188) 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-2(180-188)-specific CD8+ T cell responses. When we administered TRP-2(180-188) plus CpG ODN-containing vaccines with systemic IL-2, 18.2% of CD8+ T cells were specific for TRP-2(180-188). Identical TRP-2(180-188) plus CpG ODN vaccines given without IL-2 elicited a TRP-2(180-188)-specific CD8+ T cell response of only 1.1% of CD8+ T cells. Vaccines containing TRP-2(180-188) without CpG ODN elicited TRP-2(180-188)-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-2(180-188)-specific CD8+ T cells when IL-2 was added to TRP-2(180-188) 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.
Kochenderfer
James N
JN
Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892, USA. kochendj@mail.nih.gov
Chien
Christopher D
CD
Simpson
Jessica L
JL
Gress
Ronald E
RE
D000818:Animals; D000951:Antigens, Neoplasm; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D019496:Cancer Vaccines / Q000737:chemistry* / Q000276:immunology; D018899:CpG Islands; D004357:Drug Synergism; D018984:Epitopes, T-Lymphocyte; D007109:Immunity / Q000187:drug effects; D007376:Interleukin-2 / Q000494:pharmacology / Q000627:therapeutic use*; D019746:Intramolecular Oxidoreductases / Q000276:immunology; D008546:Melanoma, Experimental / Q000628:therapy*; D051379:Mice; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology / Q000627:therapeutic use*
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D007376:Interleukin-2; D009838:Oligodeoxyribonucleotides; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase