It has been shown that the response rate of TNBC is dependent on the level of PD-L1 and the tumor microenvironment (TME). Approaches that alter the TME can improve the efficacy of ICIs.Background: We have engineered a Smac-armed oncolytic virus by inserting a Smac transgene into the genome of a vesicular stomatitis virus to generate VSV-S. Our previous study shows that the anticancer efficacy of VSV-S is more potent than that of wild-typed VSV in a subcutaneous TNBC mouse model. VSV-S treatment reverts the immunosuppressive TME by reducing MDSCs and TAMs, while increasing infiltration of neutrophils and CD8+ T cells.Methods: VSV-S was used to treat TNBC in an orthotopic mouse model, and in a combination therapy with an anti-PD-1 antibody to treat metastatic TNBC in a mouse model. Changes in the TME were evaluated.Results: In this current study, we show that neoadjuvant VSV-S treatment of primary orthotopic TNBC tumors in mice drastically lowered lung metastasis after surgical removal of the primary tumor, and significantly increased the survival rate. The mechanism of action and changes to the TME were delineated, among which one significant marker is the elevation of PD-L1 expression in tumors. In the TNBC lung metastasis mouse model, pulmonary treatment with VSV-S greatly enhanced the efficacy of ICI treatment.Conclusions: Our results suggest that the combination of oncolytic virus and ICI therapies has the potential to substantially improve the outcome of TNBC treatment.
研究表明，三阴性乳腺癌（TNBC）的治疗反应率取决于PD-L1表达水平及肿瘤微环境（TME）状态。改变TME的策略可提升免疫检查点抑制剂（ICIs）的疗效。 背景：本研究通过将Smac转基因插入水疱性口炎病毒基因组，构建了携带Smac基因的溶瘤病毒VSV-S。前期研究显示，在皮下移植TNBC小鼠模型中，VSV-S的抗癌效果优于野生型VSV。VSV-S治疗可通过减少髓源性抑制细胞（MDSCs）和肿瘤相关巨噬细胞（TAMs），同时增加中性粒细胞和CD8+ T细胞浸润，逆转免疫抑制性TME。 方法：本研究采用VSV-S治疗原位TNBC小鼠模型，并与抗PD-1抗体联合治疗转移性TNBC小鼠模型，系统评估TME的变化。 结果：本研究发现，在小鼠原位TNBC模型中，新辅助VSV-S治疗能显著降低原发性肿瘤切除后的肺转移率，并明显提高生存率。机制研究揭示了TME的关键变化，其中PD-L1在肿瘤中的表达上调是重要标志。在TNBC肺转移小鼠模型中，肺部给予VSV-S治疗可大幅增强ICI疗法的疗效。 结论：本研究结果表明，溶瘤病毒与ICI的联合疗法有望显著改善TNBC的治疗效果。
Enhancing the Efficacy of Breast Cancer Immunotherapy Using a Smac-Armed Oncolytic Virus
肿瘤(癌症)患者之家