Vesicular stomatitis virus sensitizes immunologically cold tumors to checkpoint blockade by inducing pyroptosis.
Vesicular stomatitis virus sensitizes immunologically cold tumors to checkpoint blockade by inducing pyroptosis.
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水泡性口炎病毒通过诱导焦亡使免疫冷肿瘤对检查点封锁敏感。
DOI：
10.1016/j.bbadis.2022.166538
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发表时间：
2022-09
期刊：
影响因子：
--
通讯作者：
Wenqi He
中科院分区：
文献类型：
--
作者：
Jing Lin;Fei Liu;Fei Gao;Yujia Chen;Renling Wang;Xinyue Wang;Yue Li;Qi Li;Shihui Sun;Zi Li;Yungang Lan;Huijun Lu;Wei Guo;Li Du;Feng Gao;Deguang Song;Kui Zhao;Jiyu Guan;Wenqi He
传统上，水泡性口炎病毒（VSV）和其他溶瘤病毒（OV）被认为是通过诱导细胞凋亡来杀死肿瘤。然而，细胞凋亡导致免疫静止，这与OV激活抗肿瘤免疫微环境的能力不相容。因此，研究OVs介导的溶瘤机制对于OVs的临床应用具有重要意义。我们通过形态学观察、乳酸脱氢酶（LDH）测定、冰冻切片观察和蛋白质印迹技术检测了肿瘤细胞和组织的热凋亡。通过CRISPR/Cas9技术证实了GSDME在VSV诱导的焦亡中的关键作用。用流式细胞术检测VSV病毒治疗后肿瘤中募集的细胞毒性淋巴细胞。VSV激活的抗肿瘤免疫通过与抗PD-1抗体共同给药进一步增强。在这里，我们观察到VSV能够通过Gasdermin E（GSDME）在肿瘤细胞、人肿瘤样品和荷瘤小鼠模型中引发肿瘤细胞凋亡。重要的是，基于VSV的病毒疗法的有效性高度依赖于GSDME，因为GSDME的消耗不仅逆转VSV诱导的肿瘤抑制作用，而且降低VSV激活抗肿瘤免疫的能力。值得注意的是，VSV治疗使免疫学上的“冷”肿瘤对检查点阻断更敏感。溶瘤VSV通过激活GSDME诱导肿瘤细胞焦亡。GSDME在VSV治疗的背景下招募细胞毒性T淋巴细胞方面至关重要，这可以将免疫学上的“冷”肿瘤转变为“热”肿瘤，并增强免疫检查点治疗的功效。
Traditionally, vesicular stomatitis virus (VSV) and other oncolytic viruses (OVs) are thought to kill tumors by inducing apoptosis. However, cell apoptosis leads to immune quiescence, which is incompatible with the ability of OVs to activate the antitumor immune microenvironment. Thus, studying OVs-mediated oncolytic mechanisms is of great importance for the clinical application of OVs.We examined the pyroptosis in tumor cells and tissues by morphological observation, Lactate Dehydrogenase (LDH) assay, frozen section observation, and western-blotting techniques. The critical role of GSDME in VSV-induced pyroptosis was confirmed by CRISPR/Cas9 technique. VSV virotherapy-recruited cytotoxic lymphocytes in the tumors were examined by flow cytometry assay. VSV-activated antitumor immunity was further enhanced by the co-administration with anti-PD-1 antibody.Here, we observed that VSV was able to trigger tumor pyroptosis through Gasdermin E (GSDME) in tumor cells, human tumor samples, and tumor-bearing mouse models. Importantly, the effectiveness of VSV-based virotherapy is highly dependent on GSDME, as depletion of GSDME not only reverses VSV-induced tumor-suppressive effects but also diminishes the ability of VSV to activate antitumor immunity. Notably, VSV treatment makes immunologically 'cold' tumors more sensitive to checkpoint blockade.Oncolytic VSV induces tumor cell pyroptosis by activating GSDME. GSDME is critical in recruiting cytotoxic T lymphocytes in the context of VSV therapy, which can switch immunologically 'cold' tumors into 'hot' and enhance immune checkpoint therapy efficacy.
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DOI：
10.4049/jimmunol.0804333
发表时间：
2009-05-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Cai SF;Fehniger TA;Cao X;Mayer JC;Brune JD;French AR;Ley TJ
通讯作者：
Ley TJ
影响因子：
20.6
作者：
Wan X;Li J;Wang Y;Yu X;He X;Shi J;Deng G;Zeng X;Tian G;Li Y;Jiang Y;Guan Y;Li C;Shao F;Chen H
通讯作者：
Chen H
影响因子：
64.8
作者：
Shi, Jianjin;Zhao, Yue;Shao, Feng
通讯作者：
Shao, Feng
影响因子：
64.8
作者：
Zhang, Zhibin;Zhang, Ying;Lieberman, Judy
通讯作者：
Lieberman, Judy
DOI：
10.1073/pnas.1607769113
发表时间：
2016-07-12
影响因子：
11.1
作者：
Aglietti, Robin A.;Estevez, Alberto;Dueber, Erin C.
通讯作者：
Dueber, Erin C.