TY - JOUR
T1 - Reprogramming antitumor immunity against chemoresistant ovarian cancer by a CXCR4 antagonist-armed viral oncotherapy
AU - Komorowski, Marcin P.
AU - McGray, Aj Robert
AU - Kolakowska, Agnieszka
AU - Eng, Kevin
AU - Gil, Margaret
AU - Opyrchal, Mateusz
AU - Litwinska, Bogumila
AU - Nemeth, Michael J.
AU - Odunsi, Kunle O.
AU - Kozbor, Danuta
N1 - Funding Information:
We thank Michael F. Clarke for the pFU-Luc2-Tomato lentiviral vector, the Flow Cytometry Core and Laboratory Animal Resources for services and technical support. This work was supported in part by the National Institutes of Health grants CA164475 and Roswell Park Alliance Foundation (to D. Kozbor); the NCI-funded RPCI-UPCI Ovarian Cancer SPORE P50CA159981 (to K. Odunsi and D. Kozbor); and the NIH Cancer Center Support Grant, P30 CA016056 (to C. Johnson and K. Odunsi). M.P.K., A.J.R.M., A.K., and M.G. performed the experiments; M.J.N., M.O., K.O.O., K.E., and B.L. designed, performed data analysis and manuscript review; D.K. designed the experiments, analyzed, and interpreted the data. M.P.K. and D.K. drafted the manuscript.
PY - 2016/12/14
Y1 - 2016/12/14
N2 - 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 both in vitro and 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.
AB - 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 both in vitro and 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.
UR - http://www.scopus.com/inward/record.url?scp=85006097408&partnerID=8YFLogxK
U2 - 10.1038/mto.2016.34
DO - 10.1038/mto.2016.34
M3 - Article
C2 - 28035333
AN - SCOPUS:85006097408
SN - 2372-7705
VL - 3
SP - 16034
JO - Molecular Therapy - Oncolytics
JF - Molecular Therapy - Oncolytics
M1 - 16034
ER -