Date of Award

5-13-2021

Degree Type

Thesis

Degree Name

Master of Science (MS)

Department

Chemistry

First Advisor

Dr. Ming Luo

Abstract

Immunotherapy for treatment of pancreatic ductal adenocarcinoma (PDAC) continues to be an area of focus in the field of oncology. PDAC remains mostly incurable. The newest pillar of cancer treatments, immunotherapy, provides promises to patients as a viable option. However, the immunosuppressive microenvironment of PDAC tumors is one of the limitations on treatment efficacy. Thus, it was strategized that reactivation of the tumor’s suppressive microenvironment could lead to an increased efficacy of treatment. The use of an armed oncolytic virus (OV) to infect the tumor has shown a potential to alter the tumor microenvironment (TME) more effectively in comparison with its wildtype counterpart. Vesicular stomatitis virus (VSV) was engineered to express Smac, (VSV-S), a protein found in the intrinsic pathway of apoptosis. The ability of Smac to interact with the inhibitor of apoptosis proteins (IAPs) makes VSV-S more effective in killing cancer cells. In addition, it was determined that adapting the virus to the cell line by limited dilution increased VSV-S to selectively target the murine cancer cell, KPC. Using a C57BL/6 mice model, subcutaneous implanted KPC tumors were intratumorally injected with VSV-SKPC. After the infection by VSV-S, tumor size was greatly reduced and the survival rate was greatly increased. In the infected tumors, neutrophils were significantly increased, whereas macrophages were largely reduced, especially immunosuppressive M2-macrophages. The overall TME was also more immunologically active, which is proven by the reduced levels of cytokines and biomarkers including TGF-𝛽, Arginase -1 and IL-10. This study indicates that the treatment of VSV-S was successful in the reactivation of the immunosuppressive TME and inhibition of tumor growth.

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