CpG Are Efficient Adjuvants for Specific CTL Induction Against Tumor Antigen-Derived Peptide

Abstract

The identification of CTL-defined tumor-associated Ags has allowed the development of new strategies for cancer immunotherapy. To potentiate the CTL responses, peptide-based vaccines require the coadministration of adjuvants. Because oligodeoxynucleotides (ODN) containing CpG motifs are strong immunostimulators, we analyzed the ability of CpG ODN to act as adjuvant of the CTL response against tumor-derived synthetic peptide in the absence or presence of IFA. Mice transgenic for a chimeric MHC class I molecule were immunized with a peptide analog of MART-1/Melan-A26–35 in the presence of CpG ODN alone or CpG ODN emulsified in IFA. The CTL response was monitored ex vivo by tetramer staining of lymphocytes. In blood, spleen, and lymph nodes, peptide mixed with CpG ODN alone was able to elicit a stronger systemic CTL response as compared with peptide emulsified in IFA. Moreover, CpG ODN in combination with IFA further enhanced the CTL response in terms of the frequency of tetramer+CD8+ T cells ex vivo. The CTL induced in vivo against peptide analog in the presence of CpG ODN are functional, as they were able to recognize and kill melanoma cells in vitro. Overall, these results indicate that CpG ODN by itself is a good candidate adjuvant of CTL response and can also enhance the effect of classical adjuvant.

Characterization of the MUC1.Tg/MIN transgenic mouse as a model for studying antigen-specific immunotherapy of adenomas

“…Although some studies have showed induction of MUC1-specific antibodies in animal models and cancer patients [Reviewed in 10], our studies demonstrating the induction of CTL responses corroborate numerous reports in which CpG-ODN alone [33,37,48,49] or in combination with GM-CSF [24] were used as biologic adjuvants in peptide vaccines. A likely explanation of our results is that MHC class I-restricted MUC1 peptides which stimulate CD8 + T cells are acting in concert with CpG-ODN and GM-CSF in the vaccine cocktail to promote strong T H1 type responses resulting in the generation of efficient CTL anti-tumor responses [24,33,37,48,50]. In addition, inclusion of CpG-ODN in the vaccination cocktail in our study did not cause destruction of the lymphoid follicles or prevent isotype switching in treated mice (data not shown) as was reported by Heikenwalder, et al [51].…”

Efficient induction of T‐cell responses to carcinoembryonic antigen by a heterologous prime‐boost regimen using DNA and adenovirus vectors carrying a codon usage optimized cDNA

“…The role of immune modulation of unmethylated CpG in governing the immune response has been described both in rodents and in nonhuman primates. 48,49 Thus, as a number of CpG has been introduced into the synthetic cDNA of CEA, these may also contribute to the enhanced immunogenic properties of the CEA expressing vectors.…”

Immunostimulating capacities of stabilized RNA molecules

“…Synthetic DNA made of a stabilizing phosphorothioate backbone and containing at least one CpG motif can mimic bacterial DNA [10]. It can be added to vaccine formulations (even those already containing some other PAMP) and allow or enhance immune responses in mice and other animals (for example, apes [11][12][13]) in the context of vaccines based on DNA, peptides [14,15], proteins [16][17][18][19], virus-like particles [20], attenuated viruses [21] or inactivated bacteria [22], whether parenteral [23] or mucosal delivery of the vaccine is used [12,[24][25][26]. Moreover, synthetic immunostimulating DNA injected alone into tumors can prime a curative anti-tumor immune response by signaling danger in this otherwise "healthy" pathogenic tissue [27][28][29][30].…”