Mannose-Modified Liposome Co-Delivery of Human Papillomavirus Type 16 E7 Peptide and CpG Oligodeoxynucleotide Adjuvant Enhances Antitumor Activity Against Established Large TC-1 Grafted Tumors in Mice
Authors Zhao Y, Wang H, Yang Y, Jia W, Su T, Che Y, Feng Y, Yuan X, Wang X
Received 16 August 2020
Accepted for publication 10 November 2020
Published 1 December 2020 Volume 2020:15 Pages 9571—9586
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Dr Mian Wang
Yan Zhao, 1 Huan Wang, 2 Yang Yang, 2 Wendan Jia, 1 Tong Su, 1 Yuxin Che, 2 Yixin Feng, 1 Xuemei Yuan, 1 Xuelian Wang 2
1Department of Pharmaceutics, School of Pharmacy, China Medical University, Shenyang 110122, People’s Republic of China; 2Department of Microbiology and Parasitology, College of Basic Medical Sciences, China Medical University, Shenyang 110122, People’s Republic of China
Correspondence: Xuelian Wang Email email@example.com
Background: Previously, we demonstrated the therapeutic efficacy of a human papillomavirus (HPV) vaccine, including HPV16 E7 peptide and CpG oligodeoxynucleotides (CpG ODN), against small TC-1 grafted tumors. Here, we developed an HPV16 E7 peptide and CpG ODN vaccine delivered using liposomes modified with DC-targeting mannose, Lip E7/CpG, and determined its anti-tumor effects and influence on systemic immune responses and the tumor microenvironment (TME) in a mouse large TC-1 grafted tumor model.
Methods: L-alpha-phosphatidyl choline (SPC), cholesterol (CHOL), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy (polyethylene glycol-2000)] (DSPE-PEG-2000), 1,2-dioleoyl-3-trimethylammonium-propane chloride salt (DOTAP) and Mannose-PEG-DSPE, loaded with HPV16 E7 peptide and CpG ODN, were used to construct the Lip E7/CpG vaccine. The anti-tumor effects and potential mechanism of Lip E7/CpG were assessed by assays of tumor growth inhibition, immune cells, in vivo cytotoxic T lymphocyte (CTL) responses and cytokines, chemokines, CD31, Ki67 and p53 expression in the TME. In addition, toxicity of Lip E7/CpG to major organs was evaluated.
Results: Lip E7/CpG had a diameter of 122.21± 8.37 nm and remained stable at 4°C for 7 days. Co-delivery of HPV16 E7 peptide and CpG ODN by liposomes exerted potent anti-tumor effects in large (tumor volume ≥ 200mm 3) TC-1 grafted tumor-bearing mice with inhibition rates of 80% and 78% relative to the control and Free E7/CpG groups, respectively. Vaccination significantly increased numbers of CD4+ and CD8+ T cells, and IFN-γ-producing cells in spleens and tumors and enhanced HPV-specific CTL responses, while reducing numbers of inhibitory cells including myeloid-derived suppressor cells and macrophages. Expression of cytokines and chemokines was altered and formation of tumor blood vessels was reduced in the Lip E7/CpG group, indicating possible modulation of the immunosuppressive TME to promote anti-tumor responses. Lip E7/CpG did not cause morphological changes in major organs.
Conclusion: Lip E7/CpG induced anti-tumor effects by enhancing cellular immunity and improving tumor-associated immunosuppression. Mannose-modified liposomes are the promising vaccine delivery strategy for cancer immunotherapy.
Keywords: immunotherapy, human papillomavirus, peptide vaccine, CpG ODN adjuvant, liposome, tumor microenvironment
Corrigendum for this paper has been published