Browsing by Subject "Oncolytic virus"

ATRX is one of the most frequently altered genes in soft tissue sarcoma, with alterations occurring in 29% of these tumors. However, the role of ATRX in the development and response to cancer therapies in soft tissue sarcoma remains poorly understood. Here, we developed a primary mouse model of soft tissue sarcoma and studied the effect of Atrx deletion on tumor development and therapeutic response. Our findings demonstrate that Atrx deletion regulates tumor development and increases sarcoma sensitivity to radiation therapy. In the absence of Atrx, irradiated sarcomas have increased persistent DNA damage, telomere dysfunction, and mitotic catastrophe. We find that Atrx deleted tumors have impaired cGAS-STING signaling, with accompanying sensitivity to the novel clinical therapy oncolytic herpesvirus. Translation of these results to patients with ATRX mutant cancers could enable genomically-guided cancer therapeutic approaches that improve patient outcomes.

Viruses naturally engage innate immunity, induce antigen presentation, and mediate CD8 T cell priming against foreign antigens. Polioviruses can provide a context optimal for generating antigen-specific CD8 T cells, as they have natural tropism for dendritic cells, preeminent inducers of CD8 T cell immunity; elicit Th1-promoting inflammation; and lack interference with innate or adaptive immunity. However, notorious genetic instability and underlying neuropathogenicity has hampered poliovirus-based vector applications. We devised a strategy based on the polio:rhinovirus chimera PVSRIPO, devoid of viral neuropathogenicity after intracerebral inoculation in human subjects, for stable expression of exogenous antigens. PVSRIPO vectors infect, activate, and induce epitope presentation in DCs in vitro; recruit and activate DCs with Th1-dominant cytokine profiles at the injection site in vivo. They efficiently prime tumor antigen-specific CD8 T cells in vivo, induce CD8 T cell migration to the tumor site, delay tumor growth and enhance survival in murine tumor models.