TLR2/6 agonists and interferon-gamma induce human melanoma cells to produce CXCL10

Ileana S. Mauldin, Ena Wang, Donna H. Deacon, Walter C. Olson, Yongde Bao, Craig L. Slingluff

Research output: Contribution to journalArticle

11 Citations (Scopus)

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. What's New? Agents that boost the immune response against melanoma have shown promise in stemming the spread of disease, but their success depends on T-cell infiltration, in which chemokines recruit immune cells into the tumor microenvironment. The authors of the present study describe a novel means of stimulating the production of the T-cell-attracting chemokine CXCL10 by human melanoma cells, via the synergistic effects of toll-like receptor (TLR) agonists and interferon-gamma (IFNγ). The combined used of a TLR2/6 agonist with IFNγ significantly enhanced CXCL10 production over either treatment alone. The findings warrant further investigation of strategies to enhance T-cell infiltration in melanoma.

Original languageEnglish
Pages (from-to)1386-1396
Number of pages11
JournalInternational Journal of Cancer
Volume137
Issue number6
DOIs
Publication statusPublished - 1 Sep 2015
Externally publishedYes

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Keywords

  • immune therapy
  • melanoma
  • migration
  • toll-like receptor
  • tumor infiltration

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Mauldin, I. S., Wang, E., Deacon, D. H., Olson, W. C., Bao, Y., & Slingluff, C. L. (2015). TLR2/6 agonists and interferon-gamma induce human melanoma cells to produce CXCL10. International Journal of Cancer, 137(6), 1386-1396. https://doi.org/10.1002/ijc.29515