Exploiting Murine Cytomegalovirus as an Anti-Tumor Therapy and Model for Virus-Specific Tumor Infiltrating Lymphocytes
The immune system is tightly intertwined with tumor development, i.e. tumor immune surveillance, and can be manipulated to induce anti-tumor responses by targeting tumor immune escape pathways. Recently, it has become clear that several different escape mechanisms need to be targeted simultaneously for robust effects. This dissertation will outline the various intricacies of tumor immune surveillance and tumor immune therapies, offering new perspectives, therapies, and questions that need addressing. In this body of work, murine cytomegalovirus (MCMV) was used as an anti-tumor therapy and to model virus-specific tumor infiltrating lymphocytes (TIL). MCMV is a promising tumor vaccine vector as it induces accumulation of massive numbers of antigen-specific CD8+ T cells (i.e. memory inflation), which enter most tissues and remain functional. To explore this, MCMV expressing a modified gp100 melanoma antigen was used. Systemic vaccination was able to induce gp100-specific memory inflation, but minimal therapeutic effect. However, intratumoral delivery of MCMV significantly delayed tumor growth and prolonged survival in a CD8+ T cell-dependent, gp100-independent manner. Despite MCMV infecting and killing B16F0s in vitro, infection was restricted to tumor- associated macrophages in vivo, suggesting it was not inducing direct oncolysis. Importantly, the therapy synergized with anti-PD-L1 therapy, resulting in tumor clearance and protection in over half of the treated mice. These data demonstrate that multiple immune escape mechanisms must be targeted in order to induce tumor clearance. CD8+ TIL are correlated with positive prognosis in cancer patients. Broad phenotypic markers are used to determine TIL correlations, mostly assuming that TIL are tumor-specific. It is unknown if CD8+ T cells without tumor specificity can become TIL at steady state or in response to pathogens. To address this, tumor- specific and virus-specific CD8+ TIL were compared using MCMV-gp100 and vaccinia virus. Virus-specific CD8+ T cells migrated to tumors and became TIL in a CXCR3-dependent manner and independent of antigen during acute, cleared or latent infections. Surprisingly, virus-specific CD8+ TIL were fully functional compared to tumor-specific TIL, independent of antigen-dependent PD-1 expression. These results suggest that CD8+ TIL can reflect an individual’s immune status and may not always be tumor-specific, potentially skewing prognostic correlations.
Erkes, Dan A, "Exploiting Murine Cytomegalovirus as an Anti-Tumor Therapy and Model for Virus-Specific Tumor Infiltrating Lymphocytes" (2016). ETD Collection for Thomas Jefferson University. AAI10154385.