Interferon alpha bioactivity critically depends on Scavenger receptor class B type I function.
Scavenger receptor class B type I (SR-B1) binds pathogen-associated molecular patterns participating in the regulation of the inflammatory reaction but there is no information regarding potential interactions between SR-B1 and the interferon system. Herein, we report that SR-B1 ligands strongly regulate the transcriptional response to interferon α (IFNα) and enhance its antiviral and antitumor activity. This effect was mediated by the activation of TLR2 and TLR4 as it was annulled by the addition of anti-TLR2 or anti-TLR4 blocking antibodies. In vivo, we maximized the antitumor activity of IFNα co-expressing in the liver a SR-B1 ligand and IFNα by adeno-associated viruses. This gene therapy strategy eradicated liver metastases from colon cancer with reduced toxicity. On the other hand, genetic and pharmacological inhibition of SR-B1 blocks the clathrin-dependent interferon receptor recycling pathway with a concomitant reduction in IFNα signaling and bioactivity. This effect can be applied to enhance cancer immunotherapy with oncolytic viruses. Indeed, SR-B1 antagonists facilitate replication of oncolytic viruses amplifying their tumoricidal potential. In conclusion, SR-B1 agonists behave as IFNα enhancers while SR-B1 inhibitors dampen IFNα activity. These results demonstrate that SR-B1 is a suitable pharmacology target to enhance cancer immunotherapy based on IFNα and oncolytic viruses.
Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Navarra Institute for Health Research (IdiSNA) , Pamplona, Navarra, Spain.
Marcos
M
Vasquez
Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Navarra Institute for Health Research (IdiSNA) , Pamplona, Navarra, Spain.
Jessica
J
Fioravanti
Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Navarra Institute for Health Research (IdiSNA) , Pamplona, Navarra, Spain.
Fernando
F
Aranda
Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Navarra Institute for Health Research (IdiSNA), Pamplona, Navarra, Spain; Centro Médico Nacional La Raza, IMSS, México DF, Mexico.
Vladimir
V
Paredes
Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Navarra Institute for Health Research (IdiSNA) , Pamplona, Navarra, Spain.
Celia
C
Gomar
Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Navarra Institute for Health Research (IdiSNA) , Pamplona, Navarra, Spain.
Nuria
N
Ardaiz
Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Navarra Institute for Health Research (IdiSNA) , Pamplona, Navarra, Spain.
Veronica
V
Fernandez-Ruiz
Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Navarra Institute for Health Research (IdiSNA) , Pamplona, Navarra, Spain.
Miriam
M
Méndez
Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Navarra Institute for Health Research (IdiSNA) , Pamplona, Navarra, Spain.
Estanislao
E
Nistal-Villan
Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Navarra Institute for Health Research (IdiSNA), Pamplona, Navarra, Spain; Instituto de Salud Tropical, University of Navarra, Pamplona, Navarra, Spain.
Esther
E
Larrea
Department of Microbiology, Icahn School of Medicine at Mount Sinai , New York, NY, USA.
Qinshan
Q
Gao
Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Navarra Institute for Health Research (IdiSNA) , Pamplona, Navarra, Spain.
Gloria
G
Gonzalez-Aseguinolaza
Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Navarra Institute for Health Research (IdiSNA) , Pamplona, Navarra, Spain.
Jesus
J
Prieto
Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Navarra Institute for Health Research (IdiSNA) , Pamplona, Navarra, Spain.
Pedro
P
Berraondo
Adeno-associated virus; Newcastle disease virus; Toll-like receptor; colorectal cancer; liver metastases