Inhibitory Effects of Unmethylated CpG Oligodeoxynucleotides on MHC Class I-deficient and -proficient HPV16-associated Tumours

Unmethylated oligodeoxynucleotides containing guanine-cytidine dimers (CpG ODN) have been described as potent inducers of selected antitumour immune responses and the immunotherapeutic efficacy of CpG ODN has been examined either alone or as a vaccine adjuvant. We hypothesized that CpG ODN therapy could be an effective tool for immunotherapy of not only conventional MHC class I(+) tumours but also of those tumours that have lost MHC class I expression during their progression. To address this hypothesis, we employed the animal model resembling MHC class I-proficient and -deficient human papilloma virus (HPV) 16-associated tumours. A cell line transformed with HPV16 E6 and E7 oncogenes, TC-1, as a prototype of MHC class I-positive line, and its MHC class I-deficient sublines TC-1/A9 and TC-1/P3C10 were injected into syngeneic C57BL/6 mice and the growing tumours were subjected to immunotherapy with CpG ODN 1826. The therapy started either 1 day after the challenge with the tumour cells or later, when the tumours had reached a palpable size. In both settings, CpG ODN 1826 significantly reduced the growth of MHC class I-proficient and -deficient tumours. Furthermore, we demonstrated that CpG ODN 1585, whose mechanism of action preferably involves indirect activation of the natural killer cells, induced regression of the MHC class I-deficient tumours TC1/A9 but not of the MHC class I-proficient tumours TC-1. This study infers that synthetic CpG ODN have a potential for the therapy of both MHC class I-proficient and -deficient tumours and thus could be also used against tumours that tend to down-regulate their MHC class I expression.