A Fusion of GMCSF and IL-21 Initiates Hypersignaling Through the IL-21Rα Chain With Immune Activating and Tumoricidal Effects In Vivo

Autor: Jennifer F. Raven, Jacques Galipeau, Shala Yuan, Kathy Forner, Patrick Williams, Jessica Cuerquis, Elena Birman, Moutih Rafei, Manaf Bouchentouf
Rok vydání: 2010
Předmět:
Recombinant Fusion Proteins
T-Lymphocytes
medicine.medical_treatment
education
Melanoma
Experimental
Apoptosis
Inflammation
Biology
Cell Line
Mice
03 medical and health sciences
0302 clinical medicine
Immune system
Cancer immunotherapy
Drug Discovery
medicine
Genetics
Animals
Receptor
Molecular Biology
Cells
Cultured
health care economics and organizations
030304 developmental biology
Pharmacology
B-Lymphocytes
0303 health sciences
Interleukins
Macrophages
Granulocyte-Macrophage Colony-Stimulating Factor
Interleukin-21 Receptor alpha Subunit
Interleukin
humanities
3. Good health
Mice
Inbred C57BL
Granulocyte macrophage colony-stimulating factor
Cytokine
Immunology
Cancer research
Cytokines
Molecular Medicine
Female
Original Article
medicine.symptom
Signal Transduction
030215 immunology
medicine.drug
Zdroj: Molecular Therapy. 18(7):1293-1301
ISSN: 1525-0016
DOI: 10.1038/mt.2010.49
Popis: We hypothesized that fusing granulocyte-macrophage colony-stimulation factor (GMCSF) and interleukin (IL)-21 as a single bifunctional cytokine (hereafter GIFT-21) would lead to synergistic anticancer immune effects because of their respective roles in mediating inflammation. Mechanistic analysis of GIFT-21 found that it leads to IL-21Ralpha-dependent STAT3 hyperactivation while also contemporaneously behaving as a dominant-negative inhibitor of GMCSF-driven STAT5 activation. GIFT-21's aberrant interactions with its cognate receptors on macrophages resulted in production of 30-fold greater amounts of IL-6, TNF-alpha, and MCP-1 when compared to controls. Furthermore, GIFT-21 treatment of primary B and T lymphocytes leads to STAT1-dependent apoptosis of IL-21Ralpha(+) lymphocytes. B16 melanoma cells gene-enhanced to produce GIFT-21 were immune rejected by syngeneic C57Bl/6 mice comparable to the effect of IL-21 alone. However, a significant GIFT-21-driven survival advantage was seen when NOD-SCID mice were implanted with GIFT-21-secreting B16 cells, consistent with a meaningful role of macrophages in tumor rejection. Because GIFT-21 leads to apoptosis of IL-21Ralpha(+) lymphocytes, we tested its cytolytic effect on IL-21Ralpha(+) EL-4 lymphoma tumors implanted in C57Bl/6 mice and could demonstrate a significant increase in survival. These data indicate that GIFT-21 is a novel IL-21Ralpha agonist that co-opts IL-21Ralpha-dependent signaling in a manner permissive for targeted cancer immunotherapy.
Databáze: OpenAIRE
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