IL-18 immunoadjuvanted xenogeneic canine MMP-7 DNA vaccine overcomes immune tolerance and supresses the growth of murine mammary tumor

• Published in: International immunopharmacology Vol. 82; p. 106370
• Main Authors: Yadav, Pavan Kumar, Gupta, Shishir Kumar, Kumar, Saroj, Ghosh, Mayukh, Yadav, Brijesh Singh, Kumar, Dinesh, Kumar, Ajay, Saini, Mohini, Kataria, Meena
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.05.2020; Elsevier BV
• Subjects: Angiogenesis; Anti-tumor immune response; Antigens; Basement membranes; Cancer immunotherapy; CD4 antigen; CD8 antigen; Cytokines; Deoxyribonucleic acid; DNA; DNA vaccines; Extracellular matrix; Immune response; Immune response (cell-mediated); Immune system; Immunization; Immunological tolerance; Immunotherapy; Interleukin 1; Interleukin 18; Interleukin 2; Lymphocytes T; Mammary gland; Mammary tumor; Matrilysin; Matrix metalloproteinases; Matrix metealloproteinase-7; Matrix protein; Metastases; Proteolysis; Splenocytes; Tumorigenesis; Tumors; Vaccines; Xenogeneic DNA vaccine; γ-Interferon; Mammary tumor; Matrix metealloproteinase-7; Xenogeneic DNA vaccine; Anti-tumor immune response
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2020.106370

•Proteolysis of ECM and basement membrane by MMP-7 promotes tumorigenic invasion.•pVIVO.cMMP-7.IL-18 DNA vaccine elicits strong cellular immune response in Balb/c mice.•The xenovaccine overcomes immunological tolerance.•It exerts a potent anti-tumor response in the murine breast cancer model. The development of the tumorigenesis and angiogenesis through proteolytic cleavage of extracellular matrix protein and basement membranes is promoted by Matrix metelloproteinases-7 (MMP-7). Consequently, MMP-7 is presumed as potential target for mammary cancer immunotherapy. However, MMP-7 is an endogenous tumor associated antigen (TAA); therefore, immunization is challenging. In current study, a potent anti-tumor immune response has been elicited through recombinant bivalent plasmid pVIVO2.IL18.cMMP7 which subside the highly metastatic 4 T1 cell line induced mammary tumors and efficiently negate the existing challenge of using MMP-7 as immunotherapeutic target. Balb/c mice were immunized with canine MMP-7 (cMMP-7) using interleukine-18 (IL-18), as an immunoadjuvant, to explore the potential of the combination regarding elicitation of a potent anti-tumor immune response. Mice vaccinated with pVIVO2.IL18.cMMP7 DNA plasmid reduced the tumor growth significantly along with augmentation of the immune response to fight against tumor antigen as depicted by substantial enrichment of CD4+ and CD8+ population in splenocytes, infiltration of immune system cells in tumor tissue and enhanced survival time of mice. Further, splenocyte supernatant examination of the cytokines revealed that Th1 cytokines (IFN-γ and IL-2) were remarkably up-regulated demonstrating the stimulation of cell-mediated immune response. Thus the current observations vividly portray that administration of xenogeneic MMP-7 DNA vaccine bypasses the tolerance barrier.