Enhanced antitumor activity induced by a DNA vaccine encoding E7 antigen fused to an ERAD-targeting sequence

Abstract

The endoplasmic reticulum (ER) is a key organelle in cell homeostasis and cell health through antigen presentation to immune cells. Thus, the ER has become a therapeutic target to induce cellular immune responses. We previously reported the antitumor effect of a DNA vaccine that expresses the E7 antigen fused to the cyclooxygenase-2 (COX-2) protein. This inflammation-related enzyme contains a degradation cassette associated with the endoplasmic reticulum-associated degradation (ERAD) pathway. To avoid the use of full-length COX-2 and any risk of adverse effects due to the activity of its catalytic site, we designed new versions of the fusion protein. These new constructs encode the E7 antigen fused to the signal peptide and the ERAD sequence of COX-2 with or without the membrane-binding domain (MBD) as well as deletion of the catalytic site. We evaluated the antigen-specific antitumor effect of these DNA constructs in murine prophylactic and therapeutic cancer models. These assays showed that the ERAD cassette is the minimum sequence in the COX-2 protein that induces an antitumor effect when fused to the E7 antigen with the advantage of eliminating any potential adverse effects from the use of full-length COX-2.

Keywords:

• E7 antigen
• ER-stress
• ERAD
• cell stress
• UPR
• antitumor effect
• proteasome
• endoplasmic reticulum
• GRP78
• DNA vaccine

Acknowledgments

We would like to thank Sergio Lozano-Rodríguez, M.D. for his help in editing the text.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This manuscript was supported by Programa de Apoyo a la Investigacion Cientifica y Tecnologica (grant no. SA1904-21) from the Universidad Autonoma de Nuevo Leon. DHMP and FBA were recipients of a scholarship from CONACYT.