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

Pavan Kumar Yadav; Shishir Kumar Gupta; Saroj Kumar; Mayukh Ghosh; Brijesh Singh Yadav; Dinesh Kumar; Ajay Kumar; Mohini Saini; Meena Kataria

doi:10.1016/j.intimp.2020.106370

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

Int Immunopharmacol. 2020 Mar 7:82:106370. doi: 10.1016/j.intimp.2020.106370. Online ahead of print.

Authors

Pavan Kumar Yadav¹, Shishir Kumar Gupta², Saroj Kumar³, Mayukh Ghosh⁴, Brijesh Singh Yadav⁵, Dinesh Kumar⁶, Ajay Kumar⁷, Mohini Saini⁷, Meena Kataria⁷

Affiliations

¹ ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly 243122, Uttar Pradesh, India; Faculty of Veterinary and Animal Sciences, Rajiv Gandhi South Campus, Banaras Hindu University, Mirzapur 231001, Uttar Pradesh, India. Electronic address: pavanivri2010@gmail.com.
² ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly 243122, Uttar Pradesh, India; Laboratory Animal Facility, CSIR-CDRI, Lucknow 226031, Uttar Pradesh, India.
³ ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly 243122, Uttar Pradesh, India; Faculty of Veterinary and Animal Sciences, Rajiv Gandhi South Campus, Banaras Hindu University, Mirzapur 231001, Uttar Pradesh, India.
⁴ Faculty of Veterinary and Animal Sciences, Rajiv Gandhi South Campus, Banaras Hindu University, Mirzapur 231001, Uttar Pradesh, India.
⁵ ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly 243122, Uttar Pradesh, India; University of Information Science & Technology St. Paul the apostle Partizanska bb., 6000 Ohrid, The Former Yugolav Republic of Macedonia.
⁶ ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly 243122, Uttar Pradesh, India; College of Agriculture, Tikamgarh, Jawaharlal Nehru Krishi Vishwa Vidylaya, Jabalpur 482004, Madhya Pradesh, India.
⁷ ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly 243122, Uttar Pradesh, India.

PMID: 32155464
DOI: 10.1016/j.intimp.2020.106370

Abstract

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.

Keywords: Anti-tumor immune response; Mammary tumor; Matrix metealloproteinase-7; Xenogeneic DNA vaccine.