溶瘤病毒衍生的 I 型干扰素限制了 CAR T 细胞疗法。

Oncolytic virus-derived type I interferon restricts CAR T cell therapy.

机构信息

Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA.

Department of Immunology, Mayo Clinic, Rochester, MN, USA.

出版信息

Nat Commun. 2020 Jun 24;11(1):3187. doi: 10.1038/s41467-020-17011-z.

Abstract

The application of adoptive T cell therapies, including those using chimeric antigen receptor (CAR)-modified T cells, to solid tumors requires combinatorial strategies to overcome immune suppression associated with the tumor microenvironment. Here we test whether the inflammatory nature of oncolytic viruses and their ability to remodel the tumor microenvironment may help to recruit and potentiate the functionality of CAR T cells. Contrary to our hypothesis, VSVmIFNβ infection is associated with attrition of murine EGFRvIII CAR T cells in a B16EGFRvIII model, despite inducing a robust proinflammatory shift in the chemokine profile. Mechanistically, type I interferon (IFN) expressed following infection promotes apoptosis, activation, and inhibitory receptor expression, and interferon-insensitive CAR T cells enable combinatorial therapy with VSVmIFNβ. Our study uncovers an unexpected mechanism of therapeutic interference, and prompts further investigation into the interaction between CAR T cells and oncolytic viruses to optimize combination therapy.

摘要

过继性 T 细胞疗法的应用,包括嵌合抗原受体(CAR)修饰 T 细胞疗法,在实体瘤中需要联合策略来克服与肿瘤微环境相关的免疫抑制。在这里,我们测试了溶瘤病毒的炎症性质及其重塑肿瘤微环境的能力是否有助于招募和增强 CAR T 细胞的功能。与我们的假设相反,VSVmIFNβ 感染与在 B16EGFRvIII 模型中鼠源性 EGFRvIII CAR T 细胞的耗竭相关,尽管它诱导了趋化因子谱的强烈促炎转变。从机制上讲,感染后表达的 I 型干扰素(IFN)促进细胞凋亡、激活和抑制性受体表达,而干扰素不敏感的 CAR T 细胞使 VSVmIFNβ 能够进行组合治疗。我们的研究揭示了一种治疗干扰的意外机制,并促使进一步研究 CAR T 细胞与溶瘤病毒之间的相互作用,以优化联合治疗。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e9c2/7314766/4a0f083ca2d3/41467_2020_17011_Fig1_HTML.jpg

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