Gil Margaret, Komorowski Marcin P, Seshadri Mukund, Rokita Hanna, McGray A J Robert, Opyrchal Mateusz, Odunsi Kunle O, Kozbor Danuta
Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263;
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263;
J Immunol. 2014 Nov 15;193(10):5327-37. doi: 10.4049/jimmunol.1400201. Epub 2014 Oct 15.
Signals mediated by the chemokine CXCL12 and its receptor CXCR4 are involved in the progression of ovarian cancer through enhancement of tumor angiogenesis and immunosuppressive networks that regulate dissemination of peritoneal metastasis and development of cancer-initiating cells (CICs). In this study, we investigated the antitumor efficacy of a CXCR4 antagonist expressed by oncolytic vaccinia virus (OVV) against an invasive variant of the murine epithelial ovarian cancer cell line ID8-T. This variant harbors a high frequency of CICs that form multilayered spheroid cells and express the hyaluronan receptor CD44, as well as stem cell factor receptor CD117 (c-kit). Using an orthotopic ID8-T tumor model, we observed that i.p. delivery of a CXCR4 antagonist-expressing OVV led to reduced metastatic spread of tumors and improved overall survival compared with oncolysis alone. Inhibition of tumor growth with the armed virus was associated with efficient killing of CICs, reduced expression of ascitic CXCL12 and vascular endothelial growth factor, and decreases in i.p. numbers of endothelial and myeloid cells, as well as plasmacytoid dendritic cells. These changes, together with reduced recruitment of T regulatory cells, were associated with higher ratios of IFN-γ(+)/IL-10(+) tumor-infiltrating T lymphocytes, as well as induction of spontaneous humoral and cellular antitumor responses. Similarly, the CXCR4 antagonist released from virally infected human CAOV2 ovarian carcinoma cells inhibited peritoneal dissemination of tumors in SCID mice, leading to improved tumor-free survival in a xenograft model. Our findings demonstrate that OVV armed with a CXCR4 antagonist represents a potent therapy for ovarian CICs with a broad antitumor repertoire.
趋化因子CXCL12及其受体CXCR4介导的信号，通过增强肿瘤血管生成和免疫抑制网络参与卵巢癌进展，该网络调节腹膜转移的扩散及癌症起始细胞（CIC）的发育。在本研究中，我们调查了溶瘤痘苗病毒（OVV）表达的CXCR4拮抗剂对小鼠上皮性卵巢癌细胞系ID8-T侵袭变体的抗肿瘤疗效。该变体含有高频率的CIC，这些CIC形成多层球状体细胞并表达透明质酸受体CD44以及干细胞因子受体CD117（c-kit）。使用原位ID8-T肿瘤模型，我们观察到与单独溶瘤相比，腹腔注射表达CXCR4拮抗剂的OVV可导致肿瘤转移扩散减少并改善总体生存率。用武装病毒抑制肿瘤生长与有效杀伤CIC、腹水CXCL12和血管内皮生长因子表达降低以及腹腔内内皮细胞、髓样细胞和浆细胞样树突状细胞数量减少有关。这些变化，连同调节性T细胞募集减少，与IFN-γ(+)/IL-10(+)肿瘤浸润性T淋巴细胞的更高比例以及自发的体液和细胞抗肿瘤反应的诱导有关。同样，从病毒感染的人CAOV2卵巢癌细胞释放的CXCR4拮抗剂抑制了SCID小鼠肿瘤的腹膜扩散，导致异种移植模型中无瘤生存期延长。我们的研究结果表明，携带CXCR4拮抗剂的OVV是一种对卵巢CIC具有广泛抗肿瘤作用的有效疗法。
