Sim Chan Kyu, Cho Yeon Sook, Kim Byung Soo, Baek In-Jeoung, Kim Young-Joon, Lee Myeong Sup
Laboratory of Molecular Immunology and Medicine (MoIM), Department of Biomedical Sciences, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 138-736, Korea.
Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, 138-736, Korea.
Cancer Immunol Immunother. 2016 Jun;65(6):663-75. doi: 10.1007/s00262-016-1830-9. Epub 2016 Mar 31.
Type I interferon (IFN-I) plays a critical role in antiviral and antitumor defense. In our previous studies, we showed that IFN-I-inducible 2'-5' oligoadenylate synthetase-like 1 (OASL1) negatively regulates IFN-I production upon viral infection by specifically inhibiting translation of the IFN-I-regulating master transcription factor, interferon regulatory factor 7 (IRF7). In this study, we investigated whether OASL1 plays a negative role in the anti-tumor immune response by using OASL1-deficient (Oasl1 (-/-)) mice and transplantable syngeneic tumor cell models. We found that Oasl1 (-/-) mice demonstrate enhanced resistance to lung metastatic tumors and subcutaneously implanted tumors compared to wild-type (WT) mice. Additionally, we found that cytotoxic effector cells such as CD8(+) T cells (including tumor antigen-specific CD8(+) T cells) and NK cells as well as CD8α(+) DCs (the major antigen cross-presenting cells) were much more frequent (>fivefold) in the Oasl1 (-/-) mouse tumors. Furthermore, the cytotoxic effector cells in Oasl1 (-/-) mouse tumors seemed to be more functionally active. However, the proportion of immunosuppressive myeloid-derived suppressor cells within hematopoietic cells and of regulatory T cells within CD4(+) T cells in Oasl1 (-/-) mouse tumors did not differ significantly from that of WT mice. Tumor-challenged Oasl1 (-/-) mice expressed increased levels of IFN-I and IRF7 protein in the growing tumor, indicating that the enhanced antitumor immune response observed in Oasl1 (-/-) mice was caused by higher IFN-I production in Oasl1 (-/-) mice. Collectively, these results show that OASL1 deficiency promotes the antitumor immune response, and thus, OASL1 could be a good therapeutic target for treating tumors.
I型干扰素（IFN-I）在抗病毒和抗肿瘤防御中发挥关键作用。在我们之前的研究中，我们表明IFN-I诱导的2'-5'寡腺苷酸合成酶样1（OASL1）通过特异性抑制IFN-I调节主转录因子干扰素调节因子7（IRF7）的翻译，在病毒感染时负向调节IFN-I的产生。在本研究中，我们使用OASL1缺陷（Oasl1(-/-)）小鼠和可移植的同基因肿瘤细胞模型，研究了OASL1在抗肿瘤免疫反应中是否起负向作用。我们发现，与野生型（WT）小鼠相比，Oasl1(-/-)小鼠对肺转移瘤和皮下植入肿瘤表现出更强的抵抗力。此外，我们发现细胞毒性效应细胞，如CD8(+) T细胞（包括肿瘤抗原特异性CD8(+) T细胞）和NK细胞以及CD8α(+) DCs（主要的抗原交叉呈递细胞）在Oasl1(-/-)小鼠肿瘤中的频率要高得多（>五倍）。此外，Oasl1(-/-)小鼠肿瘤中的细胞毒性效应细胞似乎功能更活跃。然而，Oasl1(-/-)小鼠肿瘤中造血细胞内免疫抑制性髓源性抑制细胞的比例以及CD4(+) T细胞内调节性T细胞的比例与WT小鼠相比没有显著差异。受肿瘤攻击的Oasl1(-/-)小鼠在生长的肿瘤中表达的IFN-I和IRF7蛋白水平升高，表明在Oasl1(-/-)小鼠中观察到的增强的抗肿瘤免疫反应是由Oasl1(-/-)小鼠中更高的IFN-I产生引起的。总的来说，这些结果表明OASL1缺陷促进了抗肿瘤免疫反应，因此，OASL1可能是治疗肿瘤的一个良好治疗靶点。
