Oncolytic viral (OV) therapy, which uses genetically engineered tumor-targeting viruses, is being increasingly used in cancer clinical trials due to the direct cytolytic effects of this treatment that appear to provoke a robust immune response against the tumor. As OVs enter tumor cells, intrinsic host defenses have the potential to hinder viral replication and spread within the tumor mass. In this report, we show that histone deacetylase 6 (HDAC6) in tumor cells appears to alter the trafficking of post-entry OVs from the nucleus toward lysosomes. In glioma cell lines and glioma-stem–like cells, HDAC6 inhibition (HDAC6i) by either pharmacologic or genetic means substantially increased replication of oncolytic herpes simplex virus type 1 (oHSV). Moreover, HDAC6i increased shuttling of post-entry oHSV to the nucleus. In addition, electron microscopic analysis revealed that post-entry oHSVs are preferentially taken up into glioma cells through the endosomal pathway rather than via fusion at the cell surface. Together, these findings illustrate a mechanism of glioma cell defense against an incoming infection by oHSV and identify possible approaches to enhance oHSV replication and subsequent lysis of tumor cells.
Hiroshi Nakashima, Johanna K. Kaufmann, Pin-Yi Wang, Tran Nguyen, Maria-Carmela Speranza, Kazue Kasai, Kazuo Okemoto, Akihiro Otsuki, Ichiro Nakano, Soledad Fernandez, William F. Goins, Paola Grandi, Joseph C. Glorioso, Sean Lawler, Timothy P. Cripe, E. Antonio Chiocca
The HDAC6-specific inhibitor, tubacin, improves HSV-1–mediated gene expression and oHSV replication.