Dai Peihong, Wang Weiyi, Yang Ning, Serna-Tamayo Cristian, Ricca Jacob M, Zamarin Dmitriy, Shuman Stewart, Merghoub Taha, Wolchok Jedd D, Deng Liang
Dermatology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Sci Immunol. 2017 May 19;2(11). doi: 10.1126/sciimmunol.aal1713.
Advanced cancers remain a therapeutic challenge despite recent progress in targeted therapy and immunotherapy. Novel approaches are needed to alter the tumor immunosuppressive microenvironment and to facilitate the recognition of tumor antigens that leads to antitumor immunity. Poxviruses, such as modified vaccinia virus Ankara (MVA), have potential as immunotherapeutic agents. We show that infection of conventional dendritic cells (DCs) with heat- or ultraviolet-inactivated MVA leads to higher levels of interferon induction than MVA alone through the cGAS (cyclic guanosine monophosphate-adenosine monophosphate synthase)-STING cytosolic DNA-sensing pathway. Intratumoral injection of inactivated MVA (iMVA) was effective and generated adaptive antitumor immunity in murine melanoma and colon cancer models. iMVA-induced antitumor therapy was less effective in STING- or Batf3-deficient mice than in wild-type mice, indicating that both cytosolic DNA sensing and Batf3-dependent CD103/CD8α DCs are essential for iMVA immunotherapy. The combination of intratumoral delivery of iMVA and systemic delivery of immune checkpoint blockade generated synergistic antitumor effects in bilateral tumor implantation models as well as in a unilateral large established tumor model. Our results suggest that inactivated vaccinia virus could be used as an immunotherapeutic agent for human cancers.
尽管在靶向治疗和免疫治疗方面取得了最新进展，但晚期癌症仍然是一个治疗挑战。需要新的方法来改变肿瘤免疫抑制微环境，并促进对导致抗肿瘤免疫的肿瘤抗原的识别。痘病毒，如改良安卡拉痘苗病毒（MVA），具有作为免疫治疗剂的潜力。我们发现，用热灭活或紫外线灭活的MVA感染传统树突状细胞（DC），通过cGAS（环磷酸鸟苷-磷酸腺苷合酶）-STING胞质DNA感应途径，比单独使用MVA能诱导更高水平的干扰素。在小鼠黑色素瘤和结肠癌模型中，瘤内注射灭活的MVA（iMVA）是有效的，并产生了适应性抗肿瘤免疫。与野生型小鼠相比，iMVA诱导的抗肿瘤治疗在STING或Batf3缺陷小鼠中效果较差，这表明胞质DNA感应和Batf3依赖的CD103/CD8α DC对iMVA免疫治疗都至关重要。在双侧肿瘤植入模型以及单侧大型既定肿瘤模型中，瘤内递送iMVA与全身递送免疫检查点阻断剂的联合产生了协同抗肿瘤作用。我们的结果表明，灭活的痘苗病毒可作为人类癌症的免疫治疗剂。
