BACKGROUND Human papillomavirus (HPV)-associated malignancy remain a main cause of cancer in men and women. Cancer immunotherapy has represented great potential as a new promising cancer therapeutic approach. Here, we report Mesenchymal stem cells (MSCs) as a carrier for the delivery of oncolytic Newcastle disease virus (NDV) for the treatment of HPV-associated tumor. METHODS For this purpose, MSCs obtained from the bone marrow of C57BL mice, then cultured and characterized subsequently by the flow cytometry analysis for the presence of cell surface markers. In this study, we sought out to determine the impacts of MSCs loaded with oncolytic NDV on splenic T cell and cytokine immune responses, caspase-3 and -9 expression, and myeloid and myeloid-derived suppressor cells (MDSCs) by histological and immunohistochemical studies in the tumor microenvironment (TME). RESULTS Our findings proved that MSCs possess both migratory capacity and tumor tropism toward transplanted tumor tissue after peritumoral administration. Tumor therapy experiments indicated that oncolytic NDV delivered by MSCs-engineered system significantly reduces tumor growth, which is associated with the enhancement of E7-specific lymphocyte proliferation, CD8+ T cell cytolysis responses, and splenic IFN-γ, IL-4 and IL-12 responses compared with control groups. Moreover, the treatment upregulated the concentration of apoptotic proteins (caspase 9) and increased infiltration of tumor microenvironment with CD11b + myeloid and Gr1 + MDSCs cells. CONCLUSIONS Our data suggest MSCs carrying oncolytic NDV as a potentially effective strategy for cancer immunotherapy through inducing splenic Th1 immune responses and apoptosis in the tumor microenvironment.

中文翻译：

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间充质干细胞工程系统传递的溶瘤新城疫病毒增强了改变肿瘤微环境的治疗效果。

背景技术与人类乳头瘤病毒（HPV）相关的恶性肿瘤仍然是男女癌症的主要原因。癌症免疫疗法作为一种有希望的新的癌症治疗方法具有巨大的潜力。在这里，我们报告间充质干细胞（MSCs）为载体的溶瘤新城疫病毒（NDV）的治疗HPV相关肿瘤的治疗。方法为此，将从C57BL小鼠的骨髓中获得的MSCs进行培养，然后通过流式细胞术分析表征细胞表面标志物的存在。在这项研究中，我们寻求确定负载溶瘤性NDV的MSC对脾脏T细胞和细胞因子免疫应答，caspase-3和-9表达的影响，肿瘤微环境（TME）中的组织学和免疫组织化学研究，以及骨髓和髓样来源的抑制细胞（MDSCs）。结果我们的发现证明，在肿瘤周围给药后，MSC对移植的肿瘤组织具有迁移能力和肿瘤向性。肿瘤治疗实验表明，由MSCs工程系统递送的溶瘤性NDV显着降低了肿瘤的生长，这与E7特异性淋巴细胞增殖，CD8 + T细胞的细胞溶解反应以及脾脏IFN-γ，IL-4和IL-12的增强有关与对照组比较。此外，该治疗上调了凋亡蛋白（胱天蛋白酶9）的浓度，并增加了CD11b +髓样细胞和Gr1 + MDSCs细胞对肿瘤微环境的浸润。