Modulation Of Breast Tumor Associated Macrophages By Oncolytic Vesicular Stomatitis Virus

ASU Author/Contributor (non-ASU co-authors, if there are any, appear on document)
Jessica McCanless (Creator)
Institution
Appalachian State University (ASU )
Web Site: https://library.appstate.edu/
Advisor
Maryam Ahmed

Abstract: High tumor-associated macrophage (TAM) densities in cancerous breast tissue often correlates with poor clinical outcomes. This can be attributed to the M2 macrophage subtype whose wound-healing and immunosuppressive functions promote cancer cell proliferation, tumor angiogenesis, and metastasis. M2-like TAMs may thus be a suitable target for therapeutics. We are interested in developing oncolytic vesicular stomatitis virus (VSV) as a treatment option for breast cancer. VSV is cytotoxic to many breast cancer cells, including the MDA-MB-231 (MDA231) breast cancer line used in this study. We also have recent data suggesting that VSV converts model M2- like macrophages to the more immunogenic, tumor-fighting M1 profile. To model the behavior of VSV in a simulated breast tumor microenvironment (TME), aggressive MDA231 or non-aggressive T47D breast cancer cells along with model THP-1 macrophages were directly co-cultured and then infected with recombinant wild type (rwt virus) and matrix (M) protein mutant (rM51R-M virus) strains of VSV. In order to determine the macrophage phenotype under these experimental conditions, both the secretion of the M1-associated, pro-inflammatory cytokines IL-6 and TNFalpha and the M2-associated, anti-inflammatory cytokine IL-10 were monitored by ELISA. MDA231 monocultures secreted IL-6, TNFalpha, and IL-10, and these cytokine levels were reduced when the MDA231 and macrophages were cultured together. We observed that rwt virus inhibited both IL-6 and TNFalpha secretion under MDA231 co-culture conditions, but the effect was not statistically significant. The rM51R-M virus also non-significantly inhibited IL-6 production under these conditions, but enhanced TNFalpha production. Further, while rwt virus has no effect on IL-10 secretion, rM51R-M virus inhibited it under MDA231 co-culture conditions. Conversely, T47D monocultures did not secrete any of the cytokines measured. However, secretion of IL-6, TNFalpha, and IL-10 was induced when these cells were cocultured with macrophages. The rwt virus had no effect on IL-6, TNFalpha, or IL-10 production under co-culture conditions. Similarly, rM51R-M virus also did not affect the secretion of the cytokines tested, except for increasing TNFalpha production when T47D breast cancer cells were co-cultured with M1 macrophages. Results indicated that infection by VSV, especially rM51R-M virus, significantly increases co-culture secretion of TNFalpha, a known mediator of macrophage tumoricidal activities, and decreased the secretion of IL-10, a tumor-promoting cytokine, in a dose-dependent manner. This suggests that rM51R-M virus may be able to modulate the cytokine milieu of the TME to promote TAM repolarization to a pro-inflammatory, M1-like phenotype. This repolarization of TAMs has the therapeutic potential to promote destruction of the TME and to induce systemic anti-tumor memory in immune cells.

Additional Information

Publication
Thesis
McCanless, J. (2019). Modulation Of Breast Tumor Associated Macrophages By Oncolytic Vesicular Stomatitis Virus. Unpublished Master’s Thesis. Appalachian State University, Boone, NC.
Language: English
Date: 2019
Keywords
Breast Cancer, Oncolytic Virotherapy, Vesicular Stomatitis Virus, VSV, Tumor Associated Macrophages

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