Enhanced therapeutic efficacy of Listeria-based cancer vaccine with codon-optimized HPV16 E7

ABSTRACT

Cervical cancer is a leading cause of high mortality in women in developing countries and has a serious impact on women’s health. Human papilloma virus (HPV) prophylactic vaccines have been produced and may hold promise for reducing the incidence of cervical cancer. However, the limitations of current HPV vaccine strategies make the development of HPV therapeutic vaccines particularly important for the treatment of HPV related lesions. Our previous work has demonstrated that LM4Δhly::E7 was safe and effective in inducing antitumor effect by antigen-specific cellular immune responses and direct killing of tumor cell on a cervical cancer model. In this study, the codon usage effect of a novel Listeria-based cervical cancer vaccine LM4Δhly::E7-1, was evaluated for effects of codon-optimized E7 expression, cellular immune response and therapeutic efficacy in a tumor-bearing murine model. Our data demonstrated that up-regulated expression of E7 was strikingly elevated by codon usage optimization, and thus induced significantly higher Th1-biased immunity, lymphocyte proliferation, and strong specific CTL activity ex-vivo compared with LM4Δhly::E7-treated mice. Furthermore, LM4Δhly::E7-1 enhanced a remarkable therapeutic effect in establishing tumors. Taken together, our results suggest that codon usage optimization is an important consideration in constructing live bacterial-vectored vaccines and is required for promoting effective T cell responses.

KEYWORDS:

• Codon-optimized E7
• T cell immune response
• cervical cancer
• therapeutic vaccine
• attenuated Listeria monocytogenes

Disclosure of potential conflicts of interest

The authors declared that they have no conflicts of interest to this work.

We declare that we do not have any commercial or associative interest that represents a conflict of interest in connection with the work submitted.

Competing interest

The authors have declared no competing interests.

Author contributions

The project was designed by Y.Y., X.J. and Z.P., Y.Y., F.D., J. C., H.Y., Y.W., Y.J., Z.L. and Y.F. performed experiments and data analysis. Y.Y. and F.D. prepared the draft of the manuscript.

Supplementary material

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Additional information

Funding

This work was supported by the National Key R&D Programm of China [2017YFC1601201], the National Natural Science Foundation of China [No. 31472193 and 31702219], Key Research and Development Program (Modern Agriculture) Project of Jiangsu Province [BE2017341], Jiangsu Agricultural Science and Technology Innovation Funds [CX(16)1028], the Science and Technology Support Program of Jiangsu Province [BE2012367], Jiangsu Students’ Innovation and Entrepreneurship training program [201811117017Z] and the Priority Academic Development Program of Jiangsu Higher Education Institutions.