title: Oncolytic Virus-Mediated Targeting of PGE2 in the Tumor Alters the Immune Status and Sensitizes Established and Resistant Tumors to Immunotherapy.
abstract: Immunotherapies are highly promising cancer treatments, but understanding the factors mediating their resistance remains critical. Successes in randomized clinical testing have supported the growing appreciation that oncolytic virotherapies primarily act as immunotherapies. Here we identified prostaglandin E2 (PGE2) in the tumor as a key mediator of resistance to immunotherapies, including oncolytic vaccinia virotherapy. Elevated levels of PGE2 coupled to suppressive chemokine profiles and high levels of granulocytic myeloid-derived suppressor cells resulted in loss of immunotherapeutic potential. Viral vectors engineered to target PGE2 were capable of overcoming localized immunosuppression leading to profound changes in the tumor's immune status. This allowed the viral vectors to raise robust anti-tumor adaptive immune responses and sensitized established and previously resistant tumors to immunotherapies.
authors.affiliation: Department of Cell Biology, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Weizhou
authors.initials: W
authors.lastname: Hou
authors.affiliation: Department of Cell Biology, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Padma
authors.initials: P
authors.lastname: Sampath
authors.affiliation: Department of Cell Biology, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Rojas
authors.affiliation: Department of Cell Biology, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Immunology, G17a, Hillman Cancer Center, University of Pittsburgh, 5117 Center Avenue, Pittsburgh, PA 15213, USA. Electronic address: thornesh@upmc.edu.
authors.forename: Steve H
authors.initials: SH
authors.lastname: Thorne
mesh_terms: D000818:Animals; D019496:Cancer Vaccines; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D018925:Chemokines / Q000378:metabolism*; D015232:Dinoprostone / Q000037:antagonists & inhibitors*; D019008:Drug Resistance, Neoplasm; D018390:Gene Targeting / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D006911:Hydroxyprostaglandin Dehydrogenases / Q000235:genetics* / Q000494:pharmacology; D007167:Immunotherapy; D051379:Mice; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000276:immunology / Q000628:therapy*; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics / Q000276:immunology; D016019:Survival Analysis; D016896:Treatment Outcome; D014616:Vaccinia virus / Q000235:genetics
chemical_list: D019496:Cancer Vaccines; D018925:Chemokines; D006911:Hydroxyprostaglandin Dehydrogenases; D015232:Dinoprostone
keywords: COX-2; MDSC; PGE(2); immune suppression; oncolytic virus