Attenuated rabies virus promotes CNS immune infiltration and tumor necrosis in a mouse model of glioma (TUM10P.1059)

Malignant glioma is resistant to conventional treatment regimens, and recent immunotherapeutic strategies have had limited success, presumably due to lack of immune cell infiltration and function in the brain. Attenuated rabies virus (RABV) is unique in its ability to allow the therapeutic infiltration of immune cells into the CNS, hence we speculated that infection might have a beneficial effect in the GL261 mouse model of glioma. We found that infection of mice with attenuated RABV after the establishment of a GL261 CNS tumor significantly prolongs their survival. Improved survival is associated with the appearance of tumor necrosis despite the inability of the virus to replicate in the tumor. Infected tumor bearing animals also have higher levels of GL261-specific IgG2A antibody, indicating that the Th1 arm of the response has been promoted. Increased B, T and NK cell infiltration as well as elevated IFNγ and ICAM expression is also observed in CNS tissues of infected mice. In addition tumor-associated cells bearing PD-L1, FasL, CD133, and M2 markers are strikingly less abundant in the infected mice compared to uninfected controls. Our results suggest that the tumor necrosis caused by infection with RABV is the result of altered cell activity within the tumor rather than a direct effect of the virus. Increased effector presence in the CNS combined with fewer regulatory and evasive tumor-associated cells contribute to better tumor killing in RABV-infected mice.