Komorowski Marcin P, McGray Aj Robert, Kolakowska Agnieszka, Eng Kevin, Gil Margaret, Opyrchal Mateusz, Litwinska Bogumila, Nemeth Michael J, Odunsi Kunle O, Kozbor Danuta
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.
Center for Immunotherapy, Roswell Park Cancer Institute , Buffalo, New York, USA.
Mol Ther Oncolytics. 2016 Dec 14;3:16034. doi: 10.1038/mto.2016.34. eCollection 2016.
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 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.
由于发现较晚、存在内在和获得性化疗耐药以及显著的异质性，卵巢癌仍然是最致命的妇科恶性肿瘤。在此，我们探索了通过表达CXCR4拮抗剂的溶瘤痘苗病毒单独或与阿霉素联合靶向CXCL12趋化因子/CXCR4受体信号轴，来抑制对紫杉醇和卡铂耐药的小鼠和人类卵巢肿瘤变体转移生长的方法。与亲代对应物相比，耐药变体表现出透明质酸受体CD44和CXCR4的表达增加，同时Akt和ERK1/2激活升高，并且对病毒感染的易感性增加。无论是在体外培养还是在荷瘤小鼠中，感染后的培养物对阿霉素介导的杀伤更敏感。从机制上讲，联合治疗增加了与抗肿瘤免疫诱导相关的树突状细胞对肿瘤物质的凋亡和吞噬作用。用该方案靶向同基因肿瘤增加了抗肿瘤CD8 T细胞的瘤内浸润。通过病毒递送的CXCR4拮抗剂减少免疫抑制网络进一步增强了这种作用，这增强了抗肿瘤免疫反应并导致无瘤生存。我们的结果确定了治疗耐药卵巢癌的新策略，这些策略可增加免疫原性细胞死亡并逆转免疫抑制性肿瘤微环境，最终产生控制转移性肿瘤生长的抗肿瘤免疫反应。
