Deciphering the immunomodulatory capacity of oncolytic vaccinia virus to enhance the immune response to breast cancer

Author
Umer, Brittany A.
Noyce, Ryan S.
Franczak, Brian
Shenouda, Mira M.
Kelly, Rees G.
Favis, Nicole A.
Desaulniers, Megan
Baldwin, Troy A.
Hitt, Mary M.
Evans, David H.
Faculty Advisor
Date
2020
Keywords
oncolytic viruses , vaccinia virus , breast cancer , immune response , oncolytic virotherapy , interferons , tumor , VACV genome , nucleotide metabolism , chemokine
Abstract (summary)
Vaccinia virus (VACV) is a double-stranded DNA virus that devotes a large portion of its 200 kbp genome to suppressing and manipulating the immune response of its host. Here, we investigated how targeted removal of immunomodulatory genes from the VACV genome impacted immune cells in the tumor microenvironment with the intention of improving the therapeutic efficacy of VACV in breast cancer. We performed a head-to-head comparison of six mutant oncolytic VACVs, each harboring deletions in genes that modulate different cellular pathways, such as nucleotide metabolism, apoptosis, inflammation, and chemokine and interferon signaling. We found that even minor changes to the VACV genome can impact the immune cell compartment in the tumor microenvironment. Viral genome modifications had the capacity to alter lymphocytic and myeloid cell compositions in tumors and spleens, PD-1 expression, and the percentages of virus-targeted and tumor-targeted CD8+ T cells. We observed that while some gene deletions improved responses in the nonimmunogenic 4T1 tumor model, very little therapeutic improvement was seen in the immunogenic HER2/neu TuBo model with the various genome modifications. We observed that the most promising candidate genes for deletion were those that interfere with interferon signaling. Collectively, this research helped focus attention on the pathways that modulate the immune response in the context of VACV oncolytic virotherapy. They also suggest that the greatest benefits to be obtained with these treatments may not always be seen in “hot tumors.”
Publication Information
Umer B.A., Noyce R.A., Franczak B.C., Shenouda M.M., Kelly R.G., Favis N.A., Desaulniers M., Baldwin T.A., Hitt M.M., and Evans D.H. (2020) Deciphering the Immunomodulatory Capacity of Oncolytic Vaccinia Virus to Enhance the Immune Response to Breast Cancer. Cancer Immunology Research, 8(5): 615–631. https://roam.macewan.ca/islandora/object/gm%3A2989
DOI
Notes
Item Type
Article
Language
English
Rights
All Rights Reserved