Mostafa Ahmed A, Meyers Daniel E, Thirukkumaran Chandini M, Liu Peter J, Gratton Kathy, Spurrell Jason, Shi Qiao, Thakur Satbir, Morris Don G
Department of Pathology and Laboratory Medicine, University of Calgary, 2500 University Drive NW, Calgary, AB T2N 1N4, Canada.
Histocompatibility and Immunogenetics, Calgary Lab Services, 3535 Research Road NW, Calgary, AB T2L 2K8, Canada.
Cancers (Basel). 2018 Jun 15;10(6):205. doi: 10.3390/cancers10060205.
As the current efficacy of oncolytic viruses (OVs) as monotherapy is limited, exploration of OVs as part of a broader immunotherapeutic treatment strategy for cancer is necessary. Here, we investigated the ability for immune checkpoint blockade to enhance the efficacy of oncolytic reovirus (RV) for the treatment of breast cancer (BrCa). In vitro, oncolysis and cytokine production were assessed in human and murine BrCa cell lines following RV exposure. Furthermore, RV-induced upregulation of tumor cell PD-L1 was evaluated. In vivo, the immunocompetent, syngeneic EMT6 murine model of BrCa was employed to determine therapeutic and tumor-specific immune responses following treatment with RV, anti-PD-1 antibodies or in combination. RV-mediated oncolysis and cytokine production were observed following BrCa cell infection and RV upregulated tumor cell expression of PD-L1. In vivo, RV monotherapy significantly reduced disease burden and enhanced survival in treated mice, and was further enhanced by PD-1 blockade. RV therapy increased the number of intratumoral regulatory T cells, which was reversed by the addition of PD-1 blockade. Finally, dual treatment led to the generation of a systemic adaptive anti-tumor immune response evidenced by an increase in tumor-specific IFN-γ producing CD8⁺ T cells, and immunity from tumor re-challenge. The combination of PD-1 blockade and RV appears to be an efficacious immunotherapeutic strategy for the treatment of BrCa, and warrants further investigation in early-phase clinical trials.
由于溶瘤病毒（OVs）作为单一疗法的当前疗效有限，因此有必要探索将OVs作为癌症更广泛免疫治疗策略的一部分。在此，我们研究了免疫检查点阻断增强溶瘤呼肠孤病毒（RV）治疗乳腺癌（BrCa）疗效的能力。在体外，在RV暴露后人源和鼠源BrCa细胞系中评估了溶瘤作用和细胞因子产生。此外，还评估了RV诱导的肿瘤细胞PD-L1上调情况。在体内，采用具有免疫活性的同基因EMT6鼠乳腺癌模型来确定用RV、抗PD-1抗体或联合治疗后的治疗和肿瘤特异性免疫反应。在BrCa细胞感染后观察到RV介导的溶瘤作用和细胞因子产生，并且RV上调了肿瘤细胞PD-L1的表达。在体内，RV单一疗法显著减轻了治疗小鼠的疾病负担并提高了生存率，并且通过PD-1阻断进一步增强。RV治疗增加了肿瘤内调节性T细胞的数量，添加PD-1阻断可逆转这一现象。最后，联合治疗导致产生全身性适应性抗肿瘤免疫反应，表现为肿瘤特异性产生IFN-γ的CD8⁺ T细胞增加以及对肿瘤再攻击具有免疫力。PD-1阻断与RV联合似乎是一种有效的BrCa免疫治疗策略，值得在早期临床试验中进一步研究。
