Molecular Consequences of Proprotein Convertase 1/3 (PC1/3) Inhibition in Macrophages for Application to Cancer Immunotherapy: A Proteomic Study.

Abstract

Macrophages provide the first line of host immune defense. Their activation triggers the secretion of pro-inflammatory cytokines and chemokines recruiting other immune cells. In cancer, macrophages present an M2 anti-inflammatory phenotype promoting tumor growth. In this way, strategies need to be develop to reactivate macrophages. Previously thought to be expressed only in cells with a neural/neuroendocrine phenotype, the proprotein convertase 1/3 has been shown to also be expressed in macrophages and regulated as a function of the Toll-like receptor immune response. Here, we investigated the intracellular impact of the down-regulation of the proprotein convertase 1/3 in NR8383 macrophages and confirmed the results on macrophages from PC1/3 deficient mice. A complete proteomic study of secretomes and intracellular proteins was undertaken and revealed that inhibition of proprotein convertase 1/3 orient macrophages toward an M1 activated phenotype. This phenotype is characterized by filopodial extensions, Toll-like receptor 4 MyD88-dependent signaling, calcium entry augmentation and the secretion of pro-inflammatory factors. In response to endotoxin/lipopolysaccharide, these intracellular modifications increased, and the secreted factors attracted naïve T helper lymphocytes to promote the cytotoxic response. Importantly, the application of these factors onto breast and ovarian cancer cells resulted in a decrease viability or resistance. Under inhibitory conditions using interleukin 10, PC1/3-knockdown macrophages continued to secrete inflammatory factors. These data indicate that targeted inhibition of proprotein convertase 1/3 could represent a novel type of immune therapy to reactivate intra-tumoral macrophages.

• Authors: Marie Duhamel, Franck Rodet, Nadira Delhem, Fabien Vanden Abeele, Firas Kobeissy, Serge Nataf, Laurent Pays, Roxanne Desjardins, Hugo Gagnon, Maxence Wisztorski, Isabelle Fournier, Robert Day, Michel Salzet
• Journal: Molecular & cellular proteomics : MCP (Mol Cell Proteomics) Vol. 14 Issue 11 Pg. 2857-77 (Nov 2015) ISSN: 1535-9484 [Electronic] United States
• PMID: 26330543 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• Cytokines
• Lipopolysaccharides
• Myd88 protein, mouse
• Myeloid Differentiation Factor 88
• RNA, Small Interfering
• Tlr4 protein, mouse
• Toll-Like Receptor 4
• Proprotein Convertase 1
• Calcium

Topics

• Animals
• CD4-Positive T-Lymphocytes (drug effects, immunology, pathology)
• CD8-Positive T-Lymphocytes (drug effects, immunology, pathology)
• Calcium (metabolism)
• Cell Line
• Cell Line, Tumor
• Cytokines (biosynthesis, immunology)
• Gene Expression Regulation
• Humans
• Immunotherapy (methods)
• Killer Cells, Natural (drug effects, immunology, pathology)
• Lipopolysaccharides (pharmacology)
• Macrophages, Alveolar (cytology, drug effects, immunology)
• Macrophages, Peritoneal (cytology, drug effects, immunology)
• Mice
• Mice, Knockout
• Myeloid Differentiation Factor 88 (genetics, immunology)
• Primary Cell Culture
• Proprotein Convertase 1 (antagonists & inhibitors, genetics, immunology)
• Protein Array Analysis
• RNA, Small Interfering (genetics, metabolism)
• Rats
• Signal Transduction
• T-Lymphocytes, Helper-Inducer (drug effects, immunology, pathology)
• Toll-Like Receptor 4 (genetics, immunology)