Intratumoral Injection of a Human Papillomavirus Therapeutic Vaccine-Induced Strong Anti-TC-1-Grafted Tumor Activity in Mice

Cancer Management and Research

关键词: human papillomavirus;    cervical cancer;    therapeutic vaccine;    intratumoral injection;    immunosuppression;   

DOI  :  

来源: DOAJ

【 摘 要 】

Yuxin Che,1 Yang Yang,1 Jinguo Suo,1 Chang Chen,2 Xuelian Wang1 1Department of Microbiology and Parasitology, College of Basic Medical Science, China Medical University, Shenyang, Liaoning, People’s Republic of China; 2Department of Dermatology, The First Hospital of China Medical University, Shenyang, Liaoning, People’s Republic of ChinaCorrespondence: Xuelian WangDepartment of Microbiology and Parasitology, College of Basic Medical Science, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, 110122, People’s Republic of ChinaTel/Fax [phone]Email [e-mail]: The route of administration of a therapeutic tumor vaccine is a critical factor in inducing antitumor activity. In this study, we explored the effects of three vaccination routes (subcutaneous, peritumoral, and intratumoral injection) on antitumor activity induced by a human papillomavirus (HPV) therapeutic vaccine containing HPV16 E7 peptide combined with the adjuvant CpG ODN in established TC-1 grafted tumors.Methods: We used flow cytometry to evaluate splenic and tumor-infiltrating immune cells. We also assessed transcriptional changes in a sequence of immune-related genes in tumors of different treatment groups using quantitative real-time polymerase chain reaction. Immunohistochemistry was used to determine the expression of molecules related to tumor infiltrating immune cells, angiogenesis, and cancer-associated fibroblasts in tumor tissues.Results: Our results suggested that intratumoral and peritumoral vaccination generated enhanced antitumor activity compared to subcutaneous delivery. In particular, intratumoral vaccination elicited a stronger antitumor effect, with two of the six treated mice being nearly tumor-free at day 28. Three vaccination routes induced increases in splenic CD4+ and/or CD8+ T lymphocytes, and marked decreases in immunosuppressive cells. Peritumoral vaccination increased the tumor-infiltrating CD8+T cells in tumors, while intratumoral vaccination enhanced the tumor-infiltrating CD4+ and CD8+ T lymphocytes, as well as decreased the tumor-infiltrating of immunosuppressive cells, which may result in stronger inhibition of tumor growth and prolonged survival in mice bearing tumors. Furthermore, compared to the subcutaneous route, intratumoral vaccination led to a significant increase in antitumor cytokines and chemokines. In addition, our data showed marked downregulation of MMP-2, MMP-9, VEGF, CD31, and α-SMA in the intratumoral vaccination group, which might contribute to the suppression of tumor invasion, angiogenesis, and metastasis.Conclusion: Overall, intratumoral vaccination is superior to subcutaneous delivery and has the potential to inhibit tumor growth by improving the tumor microenvironment.Keywords: human papillomavirus, cervical cancer, therapeutic vaccine, intratumoral injection, immunosuppression

【 授权许可】

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