title: TLR2/6 agonists and interferon-gamma induce human melanoma cells to produce CXCL10.
abstract: Clinical approaches to treat advanced melanoma include immune therapies, whose benefits depend on tumor-reactive T-cell infiltration of metastases. However, most tumors lack significant immune infiltration prior to therapy. Selected chemokines promote T-cell migration into tumors; thus, agents that induce these chemokines in the tumor microenvironment (TME) may improve responses to systemic immune therapy. CXCL10 has been implicated as a critical chemokine supporting T-cell infiltration into the TME. Here, we show that toll-like receptor (TLR) agonists can induce chemokine production directly from melanoma cells when combined with IFNγ treatment. We find that TLR2 and TLR6 are widely expressed on human melanoma cells, and that TLR2/6 agonists (MALP-2 or FSL-1) synergize with interferon-gamma (IFNγ) to induce production of CXCL10 from melanoma cells. Furthermore, melanoma cells and immune cells from surgical specimens also respond to TLR2/6 agonists and IFNγ by upregulating CXCL10 production, compared to treatment with either agent alone. Collectively, these data identify a novel mechanism for inducing CXCL10 production directly from melanoma cells, with TLR2/6 agonists +IFNγ and raise the possibility that intratumoral administration of these agents may improve immune signatures in melanoma and have value in combination with other immune therapies, by supporting T-cell migration into melanoma metastases.
authors.affiliation: Department of Surgery, University of Virginia, Charlottesville, VA.
authors.forename: Ileana S
authors.initials: IS
authors.lastname: Mauldin
authors.affiliation: Department of Transfusion Medicine, National Institutes of Health, Bethesda, MD.
authors.forename: Ena
authors.initials: E
authors.lastname: Wang
authors.affiliation: Department of Surgery, University of Virginia, Charlottesville, VA.
authors.forename: Donna H
authors.initials: DH
authors.lastname: Deacon
authors.affiliation: Department of Surgery, University of Virginia, Charlottesville, VA.
authors.forename: Walter C
authors.initials: WC
authors.lastname: Olson
authors.affiliation: Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA.
authors.forename: Yongde
authors.initials: Y
authors.lastname: Bao
authors.affiliation: Department of Surgery, University of Virginia, Charlottesville, VA.
authors.forename: Craig L
authors.initials: CL
authors.lastname: Slingluff
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D054357:Chemokine CXCL10 / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D008545:Melanoma / Q000378:metabolism*; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000819:agonists*; D051216:Toll-Like Receptor 6 / Q000819:agonists*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; C495342:TLR2 protein, human; C495368:TLR6 protein, human; D051195:Toll-Like Receptor 2; D051216:Toll-Like Receptor 6; D007371:Interferon-gamma
keywords: immune therapy; melanoma; migration; toll-like receptor; tumor infiltration