Flores Erica B, Bartee Eric
Department of Internal Medicine, Division of Molecular Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
Mol Ther Oncolytics. 2020 Oct 27;19:323-331. doi: 10.1016/j.omto.2020.10.011. eCollection 2020 Dec 16.
Oncolytic virotherapy relies on the induction of anti-tumor immune responses to achieve therapeutic efficacy. The factors that influence the induction of these responses, however, are not well understood. To begin to address this lack of knowledge, we asked how decreasing the susceptibility of malignant cells to direct viral infection would impact the induction of immune responses and therapeutic efficacy caused by oncolytic myxoma virus treatment. To accomplish this, we used CRISPR-Cas9 genome editing to remove the essential sulfation enzyme N-deacetylase/N-sulfotransferase-1 from B16/F10 murine melanoma cells. This eliminates the negative cell surface charges associated with glycosaminoglycan sulfation, which reduces a cell's susceptibility to infection with the myxoma virus by ∼3- to 10-fold. With the use of these cells as a model of reduced susceptibility to oncolytic infection, our data demonstrate that 3- to 10-fold reductions in infection do not hinder the ability of the oncolytic myxoma virus to induce anti-tumor immunity and do not lower the overall efficacy of localized treatment. Additionally, our data show that in mice bearing multiple distinct tumor masses, the choice to treat a less-susceptible tumor mass does not reduce the overall therapeutic impact against either the injected or noninjected lesion. Taken together, these data suggest that minor changes in the susceptibility of malignant cells to direct oncolytic infection do not necessarily influence the overall outcomes of treatment.
溶瘤病毒疗法依靠诱导抗肿瘤免疫反应来实现治疗效果。然而，影响这些反应诱导的因素尚未得到充分了解。为了开始弥补这一知识空白，我们研究了降低恶性细胞对直接病毒感染的易感性将如何影响溶瘤黏液瘤病毒治疗引起的免疫反应诱导和治疗效果。为了实现这一点，我们使用CRISPR-Cas9基因组编辑技术从B16/F10小鼠黑色素瘤细胞中去除了必需的硫酸化酶N-脱乙酰酶/N-磺基转移酶-1。这消除了与糖胺聚糖硫酸化相关的负细胞表面电荷，从而使细胞对黏液瘤病毒感染的易感性降低约3至10倍。以这些细胞作为对溶瘤感染易感性降低的模型，我们的数据表明，感染降低3至10倍并不妨碍溶瘤黏液瘤病毒诱导抗肿瘤免疫的能力，也不会降低局部治疗的总体疗效。此外，我们的数据表明，在患有多个不同肿瘤块的小鼠中，选择治疗较不易感的肿瘤块不会降低对注射或未注射病变的总体治疗效果。综上所述，这些数据表明，恶性细胞对直接溶瘤感染易感性的微小变化不一定会影响治疗的总体结果。
