Laboratory Animal Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Cancer Sci. 2023 May;114(5):2158-2168. doi: 10.1111/cas.15740. Epub 2023 Feb 22.
Oncolytic virotherapy is a promising therapy for cancer. We previously established a recombinant measles virus (rMV-SLAMblind) that targets NECTIN4-expressing cancer cells and demonstrated its antitumor effects using a xenograft model in an immunodeficient mouse. In the current study, to investigate the immune response after rMV-SLAMblind therapy, we developed an immunocompetent cancer mouse model by introducing the NECTIN4 gene into mouse cancer cell lines. NECTIN4-expressing mouse cancer cells were successfully killed by rMV-SLAMblind in vitro. After transplantation of the NECTIN4-expressing tumor cells, rMV-SLAMblind significantly suppressed tumor growth in immunocompetent mice. Thus, this immunocompetent mouse cancer model could be a powerful tool in which to study the effect of rMV-SLAMblind therapy on the immune response. Using this model we found that rMV-SLAMblind elicited significant activation of natural killer cells, type 1 helper T cells and the tumor-specific CD8 T-cell response in the tumor microenvironment. Immune cell depletion study revealed that CD8 cells particularly played significant roles in the therapeutic efficacy of rMV-SLAMblind. Thus, rMV-SLAMblind exerts a therapeutic effect, not only directly by tumor cell killing, but also indirectly by efficient induction of antitumor immunity.
溶瘤病毒治疗是癌症治疗的一种有前途的方法。我们之前构建了一种靶向表达 NECTIN4 的肿瘤细胞的重组麻疹病毒（rMV-SLAMblind），并在免疫缺陷小鼠的异种移植模型中证明了其抗肿瘤作用。在本研究中，为了研究 rMV-SLAMblind 治疗后的免疫反应，我们通过将 NECTIN4 基因导入小鼠肿瘤细胞系，开发了一种免疫活性的癌症小鼠模型。rMV-SLAMblind 能够在体外有效杀伤表达 NECTIN4 的小鼠肿瘤细胞。在移植表达 NECTIN4 的肿瘤细胞后，rMV-SLAMblind 显著抑制了免疫活性小鼠的肿瘤生长。因此，这种免疫活性的小鼠癌症模型可以成为研究 rMV-SLAMblind 治疗对免疫反应影响的有力工具。使用该模型，我们发现 rMV-SLAMblind 在肿瘤微环境中引发了自然杀伤细胞、1 型辅助 T 细胞和肿瘤特异性 CD8 T 细胞反应的显著激活。免疫细胞耗竭研究表明，CD8 细胞在 rMV-SLAMblind 的治疗效果中起着重要作用。因此，rMV-SLAMblind 通过直接杀伤肿瘤细胞和有效诱导抗肿瘤免疫，发挥治疗作用。
