Melanoma-Derived Soluble DC-HIL/GPNMB Promotes Metastasis by Excluding T-Lymphocytes from the Pre-Metastatic Niches

Vijay Ramani, Takahiro Teshima, Kyoichi Tamura, Jin Sung Chung, Masato Kobayashi, Ponciano D Cruz, Kiyoshi Ariizumi

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Soluble factors from the primary tumor induce recruitment of bone marrow-derived progenitors to form tumor-supportive microenvironments or pre-metastatic niches in distal organs before metastasis. How tumor-secreted factors condition the sites for tumor progression remains ambiguous. B16 melanoma produces the secreted form of T cell-inhibitory DC-HIL (sDC-HIL) that travels to distal organs and potentiates the metastatic capacity of tumor cells. We studied the molecular mechanisms and found that sDC-HIL binds to select endothelial cells that co-localize with the sites where bone marrow-derived progenitors and tumor cells migrate. sDC-HIL–bound endothelial cells exist at a similar frequency in mice with or without tumors, and they are strongly associated with survival of intravenously injected tumor cells in the lung. sDC-HIL binding conferred T-cell suppressor function on the ECs and awakened the angiogenic property by inducing vascular endothelial growth factor expression, resulting in enhanced transendothelial migration of bone marrow-derived progenitors and tumor cells, but not for T cells. This selectivity is achieved by the T-cell binding of sDC-HIL, which prevents formation of the leading edges required for chemotaxis. Finally, inducing tumor expression of sDC-HIL significantly reduced tumor-infiltrated T cells. Therefore, the highly metastatic attribute of B16 melanoma can be explained by the endothelial gatekeeper function of sDC-HIL that limits lymphocyte transmigration to pre-metastatic niches.

Original languageEnglish (US)
Pages (from-to)2443-2451
Number of pages9
JournalJournal of Investigative Dermatology
Volume138
Issue number11
DOIs
StatePublished - Nov 2018

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Dermatology
  • Cell Biology

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