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TLR2/6 agonists and IFNlambda induce CXCL10 from melanoma

ABSTRACT: Melanoma is the most lethal form of skin cancer. Clinical efforts to combat melanoma include immune therapies whose benefit depends on antitumor T-cells, to target and to clear melanoma. However, most tumors lack significant immune infiltration prior to therapy, and some immune therapies are hindered by a persistent lack of immune-cell infiltration. Chemokines can promote T-cell migration into tumors; therefore, agents that induce T-cell attracting chemokines in the tumor microenvironment could potentially improve the clinical activity of current immune therapies for melanoma. CXCL10 has been implicated as a critical chemokine supporting T-cell infiltration into the tumor microenvironment. Here we report that combination treatment of human melanoma cell lines with Toll-like receptor (TLR) 2/6 agonists MALP-2 or FSL-1 +IFNlambda synergize to induce production of immune-cell attracting chemokines CCL3 and CXCL10 by melanoma cells. We find that TLR2 and TLR6 are widely expressed on human melanoma cells, and that stimulation of fresh patient melanoma specimens with TLR2/6 agonists+IFNlambda induces CXCL10 production from melanoma cells, endothelial and immune-cells. Furthermore, ex vivo migration assays demonstrate that stimulation of melanoma cells with TLR2/6 agonists+IFNlambda increases CD4+ and CD8+ T-cell migration toward melanoma. Collectively, these data identify a novel synergy of TLR2/6 agonists+IFNlambda for inducing CXCL10 production by melanoma cells and suggest that intralesional administration of TLR2/6 agonists+IFNlambda may improve immune signatures in melanoma metastases and have value in combination with other immune therapies, by supporting better T-cell migration to melanoma.

ORGANISM(S): Homo sapiens

PROVIDER: GSE49632 | GEO | 2015/08/13

SECONDARY ACCESSION(S): PRJNA214552

REPOSITORIES: GEO

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Project description:Differential response of bovine mammary epithelial cells to Staphylococcus aureus or Escherichia coli agonists of the innate immune system. Mastitis caused by Escherichia coli and Staphylococcus aureus is a major pathology of dairy cows. To better understand the differential response of the mammary gland to these two pathogens, we stimulated bovine mammary epithelial cells (bMEC) with either E. coli crude lipopolysaccharide (LPS) or with S. aureus culture supernatant (SaS) to compare the transcriptomic profiles of the initial bMEC response (3 and 6 h of exposure to agonists). By using HEK 293 cells transfected with human pattern recognition receptors, the LPS preparation was found to stimulate TLR2 and TLR4 but not TLR5, Nod1 or Nod2, whereas SaS stimulated TLR2. Biochemical analysis revealed that lipoteichoic acid, protein A and alpha-hemolysin were all present in SaS, and bMEC were found to be responsive to each of these molecules. Transcriptome profiling by a microarray and confirmation by RT-qPCR revealed an innate immune response which was common to both LPS and SaS. However, LPS induced expression of a significant higher number of genes and the fold changes were of greated magnitude than those induced by SaS. Overall, the analysis of microarray data suggests that the activation pathways and the early chemokine and cytokine production preceded the defense and stress responses. Chemokines were among the most up-regulated genes, in particular ELRCXC chemokines that target neutrophils. A major differential response was the activation of the type I IFN pathway by LPS but not by SaS. This was in accordance with the much stronger up-regulation of Cxcl10, Ccl5 and Nos2 by LPS than by SaS. The higher upregulation of chemokines that target mononuclear leucocytes (CXCL10, CCL2, CCL5 and CCL20) by LPS than by SaS is likely to be related to the differential activation of the type I IFN pathway, and could induce a different profile of the initial recruitment of leucocytes. It is noteworthy that at the protein level, secretion of TNF-alpha and IL-1-beta was not induced by either stimulus. These results suggest that the response of MEC to diffusible bacterial stimuli is able to contribute to the onset of the response with differential leucocyte recruitment but does not account directly for the differential production of major pro-inflammatory cytokines. Transcriptional profiling of bovine mammary epithelial cells (Holstein breed) comparing untreated control with mammary epithelial cells (MECs) stimulated by Staphylococcus aureus (SA) versus Escherichia coli lipopolysaccharide (LPS). 16 microarrays (2 stimuli * 2 times * quadruplicate) in a two-color dye-swap experimental design. Untreated cells served as the control. One replicate per array. Log2-intensity of each dye was analyzed separately => 32 samples.

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TLR2/6 agonists and IFNlambda induce CXCL10 from melanoma

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