溶瘤痘苗病毒增强了腹膜免疫，并与免疫检查点抑制剂协同抑制结直肠癌腹膜转移。
Oncolytic vaccinia virus reinvigorates peritoneal immunity and cooperates with immune checkpoint inhibitor to suppress peritoneal carcinomatosis in colon cancer.
机构信息
Department of Biomedical Science, CHA University, Seongnam, Korea (the Republic of).
Medical Oncology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea (the Republic of).
出版信息
J Immunother Cancer. 2020 Nov;8(2). doi: 10.1136/jitc-2020-000857.
BACKGROUND
Peritoneal carcinomatosis (PC) is a common and devastating manifestation of colon cancer and refractory to conventional anticancer therapeutics. During the peritoneal dissemination of colon cancer, peritoneal immunity is nullified by various mechanisms of immune evasion. Here, we employed the armed oncolytic vaccinia virus mJX-594 (JX) to rejuvenate the peritoneal antitumor immune responses in the treatment of PC.
METHODS
PC model of MC38 colon cancer was generated and intraperitoneally treated with JX and/or anti-programmed cell death protein 1 (PD-1) antibody. The peritoneal tumor burden, vascular leakage, and malignant ascites formation were then assessed. Tumors and peritoneal lavage cells were analyzed by flow cytometry, multiplex tissue imaging, and a NanoString assay.
RESULTS
JX treatment effectively suppressed peritoneal cancer progression and malignant ascites formation. It also restored the peritoneal anticancer immunity by activating peritoneal dendritic cells (DCs) and CD8 T cells. Moreover, JX selectively infected and killed peritoneal colon cancer cells and promoted the intratumoral infiltration of DCs and CD8 T cells into peritoneal tumor nodules. JX reinvigorates anticancer immunity by reprogramming immune-related transcriptional signatures within the tumor microenvironment. Notably, JX cooperates with immune checkpoint inhibitors (ICIs), anti-programmed death-1, anti-programmed death-ligand 1, and anti-lymphocyte-activation gene-3 to elicit a stronger anticancer immunity that eliminates peritoneal metastases and malignant ascites of colon cancer compared with JX or ICI alone.
CONCLUSIONS
Intraperitoneal immunotherapy with JX restores peritoneal anticancer immunity and potentiates immune checkpoint blockade to suppress PC and malignant ascites in colon cancer.
背景
腹膜癌转移（peritoneal carcinomatosis，PC）是结肠癌的一种常见且具有破坏性的表现形式，对常规抗癌治疗具有耐药性。在结肠癌腹膜扩散过程中，腹膜免疫被多种免疫逃逸机制所破坏。在此，我们利用武装溶瘤痘苗病毒 mJX-594（JX）来恢复腹膜抗肿瘤免疫反应，以治疗 PC。
方法
我们构建了 MC38 结肠癌 PC 模型，并通过腹腔内注射 JX 和/或抗程序性细胞死亡蛋白 1（PD-1）抗体进行治疗。然后评估了腹膜肿瘤负担、血管渗漏和恶性腹水形成情况。通过流式细胞术、多重组织成像和 NanoString 检测分析肿瘤和腹腔灌洗细胞。
结果
JX 治疗可有效抑制腹膜肿瘤进展和恶性腹水形成。它还通过激活腹膜树突状细胞（dendritic cells，DCs）和 CD8 T 细胞来恢复腹膜抗肿瘤免疫。此外，JX 选择性感染和杀伤腹膜结肠癌细胞，并促进 DCs 和 CD8 T 细胞向腹膜肿瘤结节内浸润。JX 通过重新编程肿瘤微环境中的免疫相关转录特征来重振抗肿瘤免疫。值得注意的是，JX 与免疫检查点抑制剂（immune checkpoint inhibitors，ICIs）、抗程序性死亡受体-1（anti-PD-1）、抗程序性死亡配体 1（anti-PD-L1）和抗淋巴细胞激活基因 3（anti-LAG-3）联合使用，可以引发更强的抗肿瘤免疫，与 JX 或 ICI 单药治疗相比，消除了结肠癌的腹膜转移和恶性腹水。
结论
腹腔内免疫治疗联合 JX 可恢复腹膜抗肿瘤免疫，并增强免疫检查点阻断，以抑制 PC 和恶性腹水的形成。
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