Tumor-associated GM-CSF overexpression induces immunoinhibitory molecules via STAT3 in myeloid-suppressor cells infiltrating liver metastases

Autor: Marissa Cunetta, N J Espat, George Miller, Richard P. Junghans, Mitchell Thorn, Steven C. Katz, Prajna Guha
Rok vydání: 2016
Předmět:
Male
STAT3 Transcription Factor
0301 basic medicine
Cancer Research
Myeloid
medicine.medical_treatment
Gene Expression
Models
Biological
B7-H1 Antigen
Immunophenotyping
Immunomodulation
Mice
03 medical and health sciences
0302 clinical medicine
Immune system
medicine
Animals
Indoleamine-Pyrrole 2
3
-Dioxygenase
Myeloid Cells
Promoter Regions
Genetic
STAT3
Molecular Biology
Regulation of gene expression
biology
Chemistry
Liver Neoplasms
Granulocyte-Macrophage Colony-Stimulating Factor
Immunosuppression
Gene Expression Regulation
Neoplastic
Disease Models
Animal
030104 developmental biology
medicine.anatomical_structure
Tumor progression
030220 oncology & carcinogenesis
Immunology
STAT protein
Cancer research
biology.protein
Molecular Medicine
Signal transduction
Biomarkers
Protein Binding
Signal Transduction
Zdroj: Cancer Gene Therapy. 23:188-198
ISSN: 1476-5500
0929-1903
Popis: Assumptions that liver immune cells and immunosuppressive pathways are similar to their counterparts in other spaces have led to gaps in our understanding of intrahepatic neoplasm aggressiveness. Myeloid-derived suppressor cells (MDSCs) are potent inhibitors of antitumor immunity and pose a major obstacle to solid tumor treatment. Liver MDSCs (L-MDSCs) associated with liver metastases (LM) are particularly problematic by contributing to intrahepatic immunosuppression that promotes tumor progression. L-MDSCs have been reported to expand in response to granulocyte-macrophages colony-stimulating factor (GM-CSF) and suppress antitumor immunity in LM. To extend these findings, we examined mechanisms of intrahepatic immunosuppression exploited by L-MDSCs. We found that the majority of L-MDSCs co-expressed GM-CSF receptor (GM-CSF-R), indoleamine 2,3-dioxygenase (IDO) and programmed death ligand 1 (PD-L1), while demonstrating high levels of signal transducer and activator of transcription factor 3 (STAT3) activation. GM-CSF-secreting tumor cells induced STAT3 phosphorylation in L-MDSCs in addition to expression of IDO and PD-L1. GM-CSF or GM-CSF-R blockade markedly reduced L-MDSC IDO and PD-L1 expression, implicating tumor-derived GM-CSF in supporting L-MDSC-immunoinhibitory molecule expression. Small-molecule inhibitors of Janus-activated kinase 2 (JAK2) and STAT3 also dramatically diminished IDO and PD-L1 expression in L-MDSCs. We determined that STAT3 exerts transcriptional control over L-MDSC IDO and PD-L1 expression by binding to the IDO1 and PD-L1 promoters. Our data suggest that the GM-CSF/JAK2/STAT3 axis in L-MDSCs drives immunosuppression in a model of LM and blockade of this pathway may enable rescue of intrahepatic antitumor immunity.
Databáze: OpenAIRE
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