Abstract
The SA-4-1BBL, an oligomeric novel form of the natural ligand for the 4-1BB co-stimulatory receptor of the tumor necrosis factor (TNF) superfamily, as a recombinant protein has potent pleiotropic effects on cells of innate, adaptive, and regulatory immunity with demonstrated therapeutic efficacy in several tumor models. However, the production of soluble form of SA-4-1BBL protein and quality control is time and resource intensive and face various issues pertinent to clinical development of biologics. The present study sought to take advantage of the simplicity and translatability of DNA-based vaccines for the production and delivery of SA-4-1BBL for cancer immune prevention and therapy. A chimeric HPV-16 E7 DNA vaccine (SP-SA-E7-4-1BBL) was constructed that contains the signal peptide (SP) of calreticulin (CRT), streptavidin (SA) domain of SA-4-1BBL, HPV-16 E7 double mutant gene, and the extracellular domain of mouse 4-1BBL. Immunization by gene gun with SP-SA-E7-4-1BBL induced greater prophylactic as well as therapeutic effects in C57BL/6 mice against TC-1 tumor model compared with immunization with E7wt, SP-SA-4-1BBL or reference-positive control CRT-E7wt. The therapeutic efficacy of the DNA vaccine was associated with increased frequency of E7-specific T cells producing interferon (IFN)-γ. Overall, our data suggest that this DNA-based vaccine strategy might represent a translational approach because it provides a simpler and versatile alternative to a subunit vaccine based on SA-4-1BBL and E7 proteins.
Highlights
The development of vaccines that modulate the innate, adaptive, and regulatory immune responses represents an attractive strategy for cancer immunotherapy
We show that signal peptide (SP)-SA-E7-4-1BBL DNA vaccine displayed robust therapeutic and prophylactic effects against HPV-16 E7-expressing TC-1 tumors when compared to controls containing either E7wt or SP-SA-4-1BBL alone
IFN-γ production, weIFN-γ evaluated cell-mediated immunity by usingimmunity a standard enzyme-linked induction of E7-specific production, we evaluated cell-mediated by using a standard immunospot (ELISpot) to monitor the ability of splenocytes immunizedfrom miceimmunized to secrete enzyme-linked immunospot assay to monitor the abilityfrom of splenocytes
Summary
The development of vaccines that modulate the innate, adaptive, and regulatory immune responses represents an attractive strategy for cancer immunotherapy. Cancers 2019, 11, 96 component of immune regulation that requires the correct functioning of a multitude of pathways such as B7-1/B7-2:CD28/CTLA-4, ICOS/ICOS ligand, CD27/CD70, 4-1BB/4-1BBL, among others. The correct modulation of these pathways provides an attractive approach to control T-cell activation and differentiation for the treatment of cancer [1,2]. 4-1BBL are an important receptor-ligand pair that belongs to TNF superfamily, where 4-1BB (CD137) is inducible on activated CD4+ and CD8+ T cells, activated dendritic cells, and activated NK and NKT cells [5,6,7]. The expression of 4-1BB ligand (4-1BBL, CD137L) occurs on mature dendritic cells as well as on macrophages and activated B cells [8,9]. The engagement of 4-1BBL with its receptor 4-1BB promotes the proliferation and survival of CD8+ T cells, prevents activation induced cell death, and induces the production of proinflammatory cytokines IL-12, IL-2, and IL-8 by dendritic cells, CD4+ T cells, and macrophages, respectively [10,11,12,13,14,15]
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