Abstract
An NK-cell–mediated immune response reduces the efficacy of oncolytic HSV glioblastoma therapy.
Major finding: An NK-cell–mediated immune response reduces the efficacy of oncolytic HSV glioblastoma therapy.
Mechanism: NK cells induce macrophage activation and clear infected tumor cells via NKp30 and NKp46.
Impact: Depletion of NK cells enhances the survival of tumor-bearing mice treated with oHSV.
An alternative approach for the treatment of glioblastoma is oncolytic virotherapy, in which viruses are engineered to specifically infect and replicate in tumor cells, resulting in subsequent lysis of infected malignant cells. However, clinical trials evaluating the use of oncolytic Herpes simplex virus (oHSV) have shown it to have limited efficacy, and the role of innate immune responses in virotherapy is controversial. Alvarez-Breckenridge and colleagues hypothesized that natural killer (NK) cells, which contribute to viral clearance at infection sites, diminish the antitumor activity of oHSV in glioblastoma. In support of this idea, activated NK cells expressing cytotoxic markers were rapidly recruited to the brains of glioblastoma-bearing mice in response to oHSV infection and replication. In addition, oHSV infection stimulated the activation of intracranial macrophages and microglial cells by inducing the expression of activation markers, including nitric oxide synthase 2, TNF, and chemokine (C-X-C motif) ligands (CXCL); this effect was dependent on IFN-γ expression and the presence of NK cells. Depletion of NK cells also resulted in increased viral titers and prolonged the survival of glioblastoma-bearing mice following treatment with tumor-specific oHSV, suggesting that NK cells impair the efficacy of virotherapy. Indeed, NK cells, but not cytotoxic T cells, preferentially killed infected tumor cells in vitro. This augmented viral clearance was mediated by the NK cell natural cytotoxicity receptors (NCR) NKp30 and NKp46 (also known as NCR3 and NCR1, respectively) and elevated NCR ligand expression on glioblastoma cells upon oHSV infection. Furthermore, Ncr1 deficiency increased HSV viral titers and adoptive transfer of Ncr1−/− NK cells enhanced the efficacy of oHSV treatment in tumor-bearing mice. These findings support a suppressive role for NK cells in virotherapy and suggest that blockade of NCRs may improve this therapeutic approach in patients with glioblastoma.
RSS Feeds