The cytokine MDA-7/IL-24 has shown potent antitumor properties in various types of cancer without exerting any significant toxicity in healthy cells. It has also been shown to encompass behavior similar to that of proimmune Th1 cytokines. Several E7 DNA vaccines have been developed against human papillomavirus (HPV)-related cervical cancer.
However, the restricted immunogenicity has limited their individual clinical applications. To address this shortcoming, we investigated whether the combination of the E7 DNA vaccine with MDA-7/IL-24 as an adjuvant would elicit efficient antitumor responses in tumor-bearing mouse models. Next, we evaluated how suppression of the immunosuppressive cytokine IL-10 would improve the outcome of our adjuvant vaccine candidate.
Methods
For this purpose, tumor-bearing mice received either the E7 DNA vaccine, the MDA-7/IL-24 cytokine, or a combination of the E7 vaccine with the MDA-7/IL-24 adjuvant one week after tumor challenge. and were boosted twice with an interval of one week. . IL-10 blockade was performed by injection of anti-IL-10 mAb before each immunization. One week after the last immunization, the mice were sacrificed and the efficacy of the treatment was evaluated by immunological and immunohistochemical analysis. In addition, the status of the tumors was monitored every other day for six-week intervals starting at week 2, and the tumor volume within different groups was measured and compared.
Results
A highly significant synergistic relationship was observed between the E7 DNA vaccine and the MDA-7/IL-24 cytokine against HPV-16+ cervical cancer models. An increase in lymphocyte proliferation, CD8+ T cell cytotoxicity, the level of Th1 cytokines (IFN-γ, TNF-α) and IL-4, the level of apoptotic markers (TRAIL and caspase-9) and a decrease.
The level of the immunosuppressive cytokine IL-10, together with the control of tumor growth and the induction of tumor regression, demonstrate the efficacy of the E7 and IL-24 adjuvant vaccine compared to their individual administration. Surprisingly, vaccination with E7 DNA and IL-24 significantly reduced the population of regulatory T cells (Treg) in the spleen of immunized mice compared to single administration and control groups. Furthermore, IL-10 blockade enhanced the effect of coadministration by eliciting higher levels of IFN-γ and caspase-9, reducing IL-10 secretion, and causing regression of tumor size.
conclusion
The synergy between the E7 DNA vaccine and MDA-7/IL-24 suggests that the low immunogenicity of DNA vaccines can be effectively addressed by combining them with an immunoregulatory agent. Furthermore, IL-10 blockade can be considered as an adjunctive treatment to improve the outcome of conventional or novel cancer therapies.
Introduction
Immunization with DNA vaccines, which express a foreign antigen, represents a simple and effective method to generate antigen-specific cellular and humoral immunity in various animal models [1, 2]. Due to cellular uptake and increased expression of antigens within host cells, DNA vaccines can stimulate specific immune responses in mouse models without causing pathogenic infections in vivo [3, 4]. However, DNA vaccines are not widely used due to their limited immunogenicity, especially in large animals and in clinical trials [5]. Therefore, various approaches have attempted to promote the immunogenicity and efficacy of DNA vaccines, particularly the incorporation of genetically encoded immune adjuvants intended to enhance the immunogenicity of antigens.