title: Reprogramming antitumor immunity against chemoresistant ovarian cancer by a CXCR4 antagonist-armed viral oncotherapy.
abstract: Ovarian cancer remains the most lethal gynecologic malignancy owing to late detection, intrinsic and acquired chemoresistance, and remarkable heterogeneity. Here, we explored approaches to inhibit metastatic growth of murine and human ovarian tumor variants resistant to paclitaxel and carboplatin by oncolytic vaccinia virus expressing a CXCR4 antagonist to target the CXCL12 chemokine/CXCR4 receptor signaling axis alone or in combination with doxorubicin. The resistant variants exhibited augmented expression of the hyaluronan receptor CD44 and CXCR4 along with elevated Akt and ERK1/2 activation and displayed an increased susceptibility to viral infection compared with the parental counterparts. The infected cultures were more sensitive to doxorubicin-mediated killing bothin vitroand in tumor-challenged mice. Mechanistically, the combination treatment increased apoptosis and phagocytosis of tumor material by dendritic cells associated with induction of antitumor immunity. Targeting syngeneic tumors with this regimen increased intratumoral infiltration of antitumor CD8+T cells. This was further enhanced by reducing the immunosuppressive network by the virally-delivered CXCR4 antagonist, which augmented antitumor immune responses and led to tumor-free survival. Our results define novel strategies for treatment of drug-resistant ovarian cancer that increase immunogenic cell death and reverse the immunosuppressive tumor microenvironment, culminating in antitumor immune responses that control metastatic tumor growth.
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York, USA; Department of Virology, National Institute of Public Health-National Institute of Hygiene, Warsaw, Poland.
authors.forename: Marcin P
authors.initials: MP
authors.lastname: Komorowski
authors.affiliation: Center for Immunotherapy, Roswell Park Cancer Institute , Buffalo, New York, USA.
authors.forename: Aj Robert
authors.initials: AR
authors.lastname: McGray
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York, USA; Department of Virology, National Institute of Public Health-National Institute of Hygiene, Warsaw, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Kolakowska
authors.affiliation: Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute , Buffalo, New York, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Eng
authors.affiliation: Department of Medicine, Roswell Park Cancer Institute , Buffalo, New York, USA.
authors.forename: Margaret
authors.initials: M
authors.lastname: Gil
authors.affiliation: Department of Medicine, Roswell Park Cancer Institute , Buffalo, New York, USA.
authors.forename: Mateusz
authors.initials: M
authors.lastname: Opyrchal
authors.affiliation: Department of Virology, National Institute of Public Health-National Institute of Hygiene , Warsaw, Poland.
authors.forename: Bogumila
authors.initials: B
authors.lastname: Litwinska
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York, USA; Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Nemeth
authors.affiliation: Center for Immunotherapy, Roswell Park Cancer Institute, Buffalo, New York, USA; Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, New York, USA.
authors.forename: Kunle O
authors.initials: KO
authors.lastname: Odunsi
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute , Buffalo, New York, USA.
authors.forename: Danuta
authors.initials: D
authors.lastname: Kozbor