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TNFa 和 IL2 编码溶瘤腺病毒激活病原体和危险相关免疫信号。

TNFa and IL2 Encoding Oncolytic Adenovirus Activates Pathogen and Danger-Associated Immunological Signaling.

机构信息

Cancer Gene Therapy Group, Faculty of Medicine, TRIMM, University of Helsinki, Haartmaninkatu 3, 00290 Helsinki, Finland.

TILT Biotherapeutics Ltd., Haartmaninkatu 3, 00290 Helsinki, Finland.

出版信息

Cells. 2020 Mar 26;9(4):798. doi: 10.3390/cells9040798.

DOI:10.3390/cells9040798
PMID:32225009
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7225950/
Abstract

In order to break tumor resistance towards traditional treatments, we investigate the response of tumor and immune cells to a novel, cytokine-armed oncolytic adenovirus: Ad5/3-d24-E2F-hTNFa-IRES-hIL2 (also known as TILT-123 and OAd.TNFa-IL2). There are several pattern recognition receptors (PRR) that might mediate adenovirus-infection recognition. However, the role and specific effects of each PRR on the tumor microenvironment and treatment outcome remain unclear. Hence, the aim of this study was to investigate the effects of OAd.TNFa-IL2 infection on PRR-mediated danger- and pathogen-associated molecular pattern (DAMP and PAMP, respectively) signaling. In addition, we wanted to see which PRRs mediate an antitumor response and are therefore relevant for optimizing this virotherapy. We determined that OAd.TNFa-IL2 induced DAMP and PAMP release and consequent tumor microenvironment modulation. We show that the AIM2 inflammasome is activated during OAd.TNFa-IL2 virotherapy, thus creating an immunostimulatory antitumor microenvironment.

摘要

为了打破肿瘤对传统治疗的耐药性，我们研究了新型细胞因子武装的溶瘤腺病毒 Ad5/3-d24-E2F-hTNFa-IRES-hIL2（也称为 TILT-123 和 OAd.TNFa-IL2）对肿瘤和免疫细胞的反应。有几种模式识别受体（PRR）可能介导腺病毒感染的识别。然而，每种 PRR 在肿瘤微环境和治疗结果中的作用和具体影响仍不清楚。因此，本研究旨在研究 OAd.TNFa-IL2 感染对 PRR 介导的危险相关和病原体相关分子模式（DAMP 和 PAMP）信号的影响。此外，我们还想了解哪些 PRR 介导抗肿瘤反应，因此对于优化这种病毒疗法具有重要意义。我们确定 OAd.TNFa-IL2 诱导了 DAMP 和 PAMP 的释放，并因此调节了肿瘤微环境。我们表明，在 OAd.TNFa-IL2 病毒治疗期间，AIM2 炎性小体被激活，从而创造了一个免疫刺激性的抗肿瘤微环境。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d51/7225950/d9fa7c58eb8e/cells-09-00798-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d51/7225950/0dc7192e35db/cells-09-00798-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d51/7225950/c63779c915b4/cells-09-00798-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d51/7225950/dd9222e9d490/cells-09-00798-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d51/7225950/4c48167d97e7/cells-09-00798-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d51/7225950/d9fa7c58eb8e/cells-09-00798-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d51/7225950/0dc7192e35db/cells-09-00798-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d51/7225950/c63779c915b4/cells-09-00798-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d51/7225950/dd9222e9d490/cells-09-00798-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d51/7225950/4c48167d97e7/cells-09-00798-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d51/7225950/d9fa7c58eb8e/cells-09-00798-g005.jpg

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Effect of Genetic Modifications on Physical and Functional Titers of Adenoviral Cancer Gene Therapy Constructs.
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