Development and Evaluation of mRNA Cancer Vaccines in HPV-Driven Tumors and Chronic Inflammation

다국어 초록 (Multilingual Abstract)

HPV-associated cancers, such as cervical and oropharyngeal cancers, remain a major global health problem with limited conventional therapeutic options including surgery, chemotherapy, or radiotherapy. Messenger RNA (mRNA) vaccines represent a promising technology owing to their safety and ability to elicit strong immune responses. This dissertation investigated the efficacy of HPV-targeted mRNA vaccines, their adverse effects under chronic inflammatory conditions, and strategies to overcome the immunosuppressive tumor microenvironment. In animal studies using TC-1 tumor–bearing mice, an mRNA vaccine (mHTV) encoding HPV16/18 E6 and E7 antigens induced potent CD8⁺ T cell responses, robust immune cell infiltration, and marked tumor regression. Furthermore, mRNA immunization conferred durable protection against tumor re-challenge up to 160 days after vaccination, while nonhuman primates exhibited strong antigen-specific T cell responses, confirming translational potential. However, in a chronic inflammation model generated by continuous lipopolysaccharide infusion, mRNA vaccination induced myocarditis and impaired muscle mitochondrial regulation. Although humoral immunity was preserved, cellular immune responses particularly T cell activation were attenuated, suggesting compromised efficacy and increased risk in inflammatory conditions. Insufficient immune responses under inflammatory conditions are also observed in the mEER cancer mouse model. This can be addressed by co-delivery of interleukin-12 (IL-12) mRNA, which significantly enhances antigen presentation, promotes CD8⁺ T cell cytotoxicity, and strengthens antitumor immunity in HPV-positive head and neck cancer models. Overall, these findings demonstrate that HPV-targeted mRNA vaccines possess both therapeutic and prophylactic efficacy but may exhibit reduced performance under chronic inflammation. Incorporation of IL-12 as a molecular adjuvant provides a promising strategy to overcome immune suppression and maximize clinical benefit. This work highlights the potential of mRNA vaccines as next-generation immunotherapies for HPV-associated malignancies.

목차 (Table of Contents)

• Ⅰ. Overall Abstract 1
• Ⅱ. Overall Introduction 3
• Ⅲ. Chapter 1. Subcutaneous mRNA-HPV vaccination shows prophylactic and
• therapeutic potential in mice and NHPs 29
• Abstract 30
• Introduction 31
• Materials & Methods 34
• Result 41
• Discussion 62
• Ⅳ. Chapter 2. Impact of chronic inflammation on the adverse effects and
• immunogenicity of mRNA vaccines 65
• Abstract 66
• Introduction 67
• Materials & Methods 70
• Result 76
• Discussion 86
• Ⅴ. Chapter 3. Therapeutic evaluation of mRNA encoding E7 or IL-12 in head and
• neck cancer using a murine tumor model 89
• Abstract 90
• Introduction 91
• Materials & Methods 94
• Result 100
• Discussion 114
• Ⅵ. Overall Discussion 118
• Ⅶ. REFERENCES 125