Cytomegalovirus-induced oncomodulation drives immune escape in glioblastoma.

Immune evasion and suppression lead to unchecked tumor growth in glioblastoma. Cytomegalovirus (CMV) has been implicated in tumor progression and modulation in glioblastoma. To investigate this potential connection, CMV-associated changes in the glioblastoma immune landscape were characterized in vitro and in a murine glioblastoma model. Infection of mouse glioblastoma cells (GL261Luc2) with mCMV resulted in a short period of viral replication. MHC-I cell surface expression was reduced after mCMV infection by approximately 40% compared with non-infected tumor cells (p < 0.0001). Viral regulators of antigen presentation (vRAP) were shown to be responsible for MHC-I downregulation using a recombinant mCMV (ΔvRAP) lacking the known immune evasion genes. RNA sequencing of mCMV infected GL261Luc cells revealed 2711 differentially expressed genes (p < 0.005). Of particular interest was the downregulation of MHC-I-associated genes H2-Q1-10 and Tap1 fter CMV infection. In vivo, the mCMV immediate early gene (IE1) was detected in brains of mCMV + animals after tumor implantation and increased during tumor growth. mCMV + mice had significantly shorter survival than controls, depending on initial tumor size (P < 0.001). Tumor immune infiltrates in mCMV infection were characterized by B cell infiltrates and low levels of NK cell infiltration. Here, the landscape of immune cell infiltrates is shifted toward B cell infiltration and reduced numbers of NK cells. CMV leads to immune evasion mediated MHC-I downregulation in murine glioblastoma. Thus, CMV infection in glioblastoma may contribute to unchecked tumor growth in glioblastoma by increasing immune evasion.