OX40L 表达的重组改良安卡拉痘苗病毒通过重编程 Tregs 诱导有效的抗肿瘤免疫。

OX40L-expressing recombinant modified vaccinia virus Ankara induces potent antitumor immunity via reprogramming Tregs.

机构信息

Department of Medicine, Dermatology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

The Laboratory of Virology and Infectious Disease, The Rockefeller University , New York, NY, USA.

出版信息

J Exp Med. 2023 Aug 7;220(8). doi: 10.1084/jem.20221166. Epub 2023 May 5.

Effective depletion of immune suppressive regulatory T cells (Tregs) in the tumor microenvironment without triggering systemic autoimmunity is an important strategy for cancer immunotherapy. Modified vaccinia virus Ankara (MVA) is a highly attenuated, non-replicative vaccinia virus with a long history of human use. Here, we report rational engineering of an immune-activating recombinant MVA (rMVA, MVA∆E5R-Flt3L-OX40L) with deletion of the vaccinia E5R gene (encoding an inhibitor of the DNA sensor cyclic GMP-AMP synthase, cGAS) and expression of two membrane-anchored transgenes, Flt3L and OX40L. Intratumoral (IT) delivery of rMVA (MVA∆E5R-Flt3L-OX40L) generates potent antitumor immunity, dependent on CD8+ T cells, the cGAS/STING-mediated cytosolic DNA-sensing pathway, and type I IFN signaling. Remarkably, IT rMVA (MVA∆E5R-Flt3L-OX40L) depletes OX40hi regulatory T cells via OX40L/OX40 interaction and IFNAR signaling. Single-cell RNA-seq analyses of tumors treated with rMVA showed the depletion of OX40hiCCR8hi Tregs and expansion of IFN-responsive Tregs. Taken together, our study provides a proof-of-concept for depleting and reprogramming intratumoral Tregs via an immune-activating rMVA.

在不引发系统性自身免疫的情况下，有效耗尽肿瘤微环境中的免疫抑制性调节性 T 细胞（Tregs）是癌症免疫治疗的重要策略。改良安卡拉牛痘病毒（MVA）是一种高度减毒、非复制的牛痘病毒，具有悠久的人类使用历史。在这里，我们报告了一种具有免疫激活功能的重组 MVA（rMVA，MVA∆E5R-Flt3L-OX40L）的合理工程设计，该重组 MVA 缺失了牛痘 E5R 基因（编码一种 DNA 传感器环鸟苷酸-腺苷酸合酶（cGAS）的抑制剂），并表达了两种膜锚定的转基因，Flt3L 和 OX40L。肿瘤内（IT）递送 rMVA（MVA∆E5R-Flt3L-OX40L）可产生强大的抗肿瘤免疫，依赖于 CD8+T 细胞、cGAS/STING 介导的细胞质 DNA 感应途径和 I 型 IFN 信号。值得注意的是，IT rMVA（MVA∆E5R-Flt3L-OX40L）通过 OX40L/OX40 相互作用和 IFNAR 信号耗竭 OX40hi 调节性 T 细胞。用 rMVA 治疗的肿瘤的单细胞 RNA-seq 分析显示，OX40hiCCR8hi Tregs 被耗竭，IFN 反应性 Tregs 被扩增。总之，我们的研究为通过免疫激活 rMVA 耗竭和重编程肿瘤内 Tregs 提供了一个概念验证。