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.
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。
