Tang Sijia, Lyles Kristin V, Wang Yuzhen, Fan Daping, Luo Ming
Institute of Biomedical Sciences, Georgia State University, Atlanta, GA 30302, USA.
Department of Chemistry, Georgia State University, Atlanta, GA 30302, USA.
Cancers (Basel). 2024 Sep 24;16(19):3248. doi: 10.3390/cancers16193248.
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. : 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. : 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. : 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. : 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）的反应率取决于程序性死亡受体配体1（PD-L1）水平和肿瘤微环境（TME）。改变肿瘤微环境的方法可以提高免疫检查点抑制剂（ICIs）的疗效。我们通过将Smac转基因插入水疱性口炎病毒基因组中构建了一种携带Smac的溶瘤病毒，即VSV-S。我们之前的研究表明，在皮下TNBC小鼠模型中，VSV-S的抗癌效果比野生型VSV更强。VSV-S治疗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细胞的浸润，逆转免疫抑制性肿瘤微环境。VSV-S被用于原位小鼠模型中治疗TNBC，并与抗PD-1抗体联合用于小鼠模型中治疗转移性TNBC。评估了肿瘤微环境的变化。在本研究中，我们表明，对小鼠原发性原位TNBC肿瘤进行新辅助VSV-S治疗，在手术切除原发性肿瘤后可显著降低肺转移，并显著提高生存率。阐明了其作用机制和肿瘤微环境的变化，其中一个重要标志是肿瘤中PD-L1表达的升高。在TNBC肺转移小鼠模型中，用VSV-S进行肺部治疗大大增强了ICIs治疗的疗效。我们的结果表明，溶瘤病毒和ICIs疗法联合应用有可能显著改善TNBC的治疗效果。
