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.

中文翻译：

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通过CXCR4拮抗剂武装的病毒癌疗法重新编程针对化学耐药性卵巢癌的抗肿瘤免疫力。

由于发现较晚，内在性和获得性化学耐药性以及显着的异质性，卵巢癌仍然是最致命的妇科恶性肿瘤。在这里，我们探索了通过表达CXCR4拮抗剂的溶瘤牛痘病毒单独或与阿霉素组合靶向CXCL12趋化因子/ CXCR4受体信号传导轴来抑制对紫杉醇和卡铂耐药的鼠类和人卵巢肿瘤变体转移生长的方法。与亲本相比，抗性变体表现出乙酰透明质酸受体CD44和CXCR4的表达增加，以及Akt和ERK1 / 2的活化增加，并且对病毒感染的敏感性更高。受感染的培养物对阿霉素介导的体外杀伤和肿瘤攻击小鼠的杀伤更为敏感。机械上，联合治疗增加了树突状细胞的凋亡和吞噬吞噬作用，并诱导了抗肿瘤免疫力。用这种方案靶向同系肿瘤会增加抗肿瘤CD8 + T细胞的肿瘤内浸润。通过减少病毒输送的CXCR4拮抗剂的免疫抑制网络可进一步增强这种免疫抑制网络，从而增强抗肿瘤免疫反应并导致无肿瘤生存。我们的结果确定了治疗耐药性卵巢癌的新策略，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，最终达到控制转移性肿瘤生长的抗肿瘤免疫反应。用这种方案靶向同系肿瘤会增加抗肿瘤CD8 + T细胞的肿瘤内浸润。通过减少病毒输送的CXCR4拮抗剂的免疫抑制网络可进一步增强这种免疫抑制网络，从而增强抗肿瘤免疫反应并导致无肿瘤生存。我们的结果确定了治疗耐药性卵巢癌的新策略，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，最终达到控制转移性肿瘤生长的抗肿瘤免疫反应。用这种方案靶向同系肿瘤会增加抗肿瘤CD8 + T细胞的肿瘤内浸润。通过减少病毒输送的CXCR4拮抗剂的免疫抑制网络可进一步增强这种免疫抑制网络，从而增强抗肿瘤免疫反应并导致无肿瘤生存。我们的结果确定了治疗耐药性卵巢癌的新策略，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，最终达到控制转移性肿瘤生长的抗肿瘤免疫反应。