Type I interferons exert anti-tumor effect via reversing immunosuppression mediated by mesenchymal stromal cells.
Mesenchymal stromal cells (MSCs) are strongly immunosuppressive via producing nitric oxide (NO) and known to migrate into tumor sites to promote tumor growth, but the underlying mechanisms remain largely elusive. Here, we found that interferon alpha (IFNα)-secreting MSCs showed more dramatic inhibition effect on tumor progression than that of IFNα alone. Interestingly, IFNα-primed MSCs could also effectively suppress tumor growth. Mechanistically, we demonstrated that both IFNα and IFNβ (type I IFNs) reversed the immunosuppressive effect of MSCs on splenocyte proliferation. This effect of type I IFNs was exerted through inhibiting inducible NO synthase (iNOS) expression in IFNγ and TNFα-stimulated MSCs. Notably, only NO production was inhibited by IFNα; production of other cytokines or chemokines tested was not suppressed. Furthermore, IFNα promoted the switch from signal transducer and activator of transcription 1 (Stat1) homodimers to Stat1-Stat2 heterodimers. Studies using the luciferase reporter system and chromatin immunoprecipitation assay revealed that IFNα suppressed iNOS transcription through inhibiting the binding of Stat1 to iNOS promoter. Therefore, the synergistic anti-tumor effects of type I IFNs and MSCs were achieved by inhibiting NO production. This study provides essential information for understanding the mechanisms of MSC-mediated immunosuppression and for the development of better clinical strategies using IFNs and MSCs for cancer immunotherapy.
Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China.|University of Chinese Academy of Sciences, Beijing, China.
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P
Shou
Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China.|The First Affiliated Hospital of Soochow University, Institutes for Translational Medicine, Soochow University, Suzhou, Jiangsu, China.
Q
Q
Chen
The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China.
J
J
Jiang
Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China.
C
C
Xu
Child Health Institute of New Jersey, Robert-Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA.
J
J
Zhang
Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China.
C
C
Zheng
Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China.
M
M
Jiang
Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China.
T
T
Velletri
Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China.
W
W
Cao
Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Y
Y
Huang
Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Q
Q
Yang
Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China.
X
X
Han
The First Affiliated Hospital of Soochow University, Institutes for Translational Medicine, Soochow University, Suzhou, Jiangsu, China.|Child Health Institute of New Jersey, Robert-Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA.
L
L
Zhang
Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China.
L
L
Wei
Child Health Institute of New Jersey, Robert-Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA.
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AB
Rabson
Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Y E
YE
Chin
Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Y
Y
Wang
Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China.|The First Affiliated Hospital of Soochow University, Institutes for Translational Medicine, Soochow University, Suzhou, Jiangsu, China.|Child Health Institute of New Jersey, Robert-Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA.
Y
Y
Shi
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015415:Biomarkers; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects*; D007370:Interferon Type I / Q000378:metabolism* / Q000494:pharmacology*; D008546:Melanoma, Experimental; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D015415:Biomarkers; D016207:Cytokines; D007370:Interferon Type I; D009569:Nitric Oxide