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)
Appalachian State University (ASU )
Web Site:
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

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
Breast Cancer, Oncolytic Virotherapy, Vesicular Stomatitis Virus, VSV, Tumor Associated Macrophages

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