title: 2'-5' Oligoadenylate synthetase-like 1 (OASL1) deficiency in mice promotes an effective anti-tumor immune response by enhancing the production of type I interferons.
abstract: 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.
authors.affiliation: 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.
authors.forename: Chan Kyu
authors.initials: CK
authors.lastname: Sim
authors.affiliation: 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.
authors.forename: Yeon Sook
authors.initials: YS
authors.lastname: Cho
authors.affiliation: 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.
authors.forename: Byung Soo
authors.initials: BS
authors.lastname: Kim
authors.affiliation: Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, 138-736, Korea.|KMPC (Korea Mouse Phenotyping Center), Seoul, 151-742, Korea.
authors.forename: In-Jeoung
authors.initials: IJ
authors.lastname: Baek
authors.affiliation: Department of Biochemistry, College of Life Science and Technology, Yonsei University, Seoul, 120-749, Korea.
authors.forename: Young-Joon
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: 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. myeong@amc.seoul.kr.|KMPC (Korea Mouse Phenotyping Center), Seoul, 151-742, Korea. myeong@amc.seoul.kr.
authors.forename: Myeong Sup
authors.initials: MS
authors.lastname: Lee
mesh_terms: D015088:2',5'-Oligoadenylate Synthetase / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D003601:Cytotoxicity Tests, Immunologic; D004195:Disease Models, Animal; D007109:Immunity / Q000235:genetics*; D016130:Immunophenotyping; D050839:Interferon Regulatory Factor-7 / Q000378:metabolism; D007370:Interferon Type I / Q000096:biosynthesis*; D008175:Lung Neoplasms / Q000276:immunology / Q000556:secondary; D018655:Lymphocyte Count; D016131:Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D008546:Melanoma, Experimental; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000209:etiology* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology
chemical_list: D050839:Interferon Regulatory Factor-7; D007370:Interferon Type I; C475083:Oasl1 protein, mouse; D015088:2',5'-Oligoadenylate Synthetase
keywords: Anti-tumor immune response; Negative regulator; OASL1; Therapeutic target; Type I interferon