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Smac mimetics and oncolytic viruses synergize in driving anticancer T-cell responses through complementary mechanisms

Second mitochondrial activator of caspase (Smac)-mimetic compounds and oncolytic viruses were developed to kill cancer cells directly. However, Smac-mimetic compound and oncolytic virus therapies also modulate host immune responses in ways we hypothesized would complement one another in promoting an...

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Detalles Bibliográficos
Autores principales: Kim, Dae-Sun, Dastidar, Himika, Zhang, Chunfen, Zemp, Franz J., Lau, Keith, Ernst, Matthias, Rakic, Andrea, Sikdar, Saif, Rajwani, Jahanara, Naumenko, Victor, Balce, Dale R., Ewanchuk, Ben W., Tailor, Pankaj, Yates, Robin M., Jenne, Craig, Gafuik, Chris, Mahoney, Douglas J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5570934/
https://www.ncbi.nlm.nih.gov/pubmed/28839138
http://dx.doi.org/10.1038/s41467-017-00324-x
Descripción
Sumario:Second mitochondrial activator of caspase (Smac)-mimetic compounds and oncolytic viruses were developed to kill cancer cells directly. However, Smac-mimetic compound and oncolytic virus therapies also modulate host immune responses in ways we hypothesized would complement one another in promoting anticancer T-cell immunity. We show that Smac-mimetic compound and oncolytic virus therapies synergize in driving CD8(+) T-cell responses toward tumors through distinct activities. Smac-mimetic compound treatment with LCL161 reinvigorates exhausted CD8(+) T cells within immunosuppressed tumors by targeting tumor-associated macrophages for M1-like polarization. Oncolytic virus treatment with vesicular stomatitis virus (VSV(ΔM51)) promotes CD8(+) T-cell accumulation within tumors and CD8(+) T-cell activation within the tumor-draining lymph node. When combined, LCL161 and VSV(ΔM51) therapy engenders CD8(+) T-cell-mediated tumor control in several aggressive mouse models of cancer. Smac-mimetic compound and oncolytic virus therapies are both in clinical development and their combination therapy represents a promising approach for promoting anticancer T-cell immunity.