Defective FasL expression is associated with increased resistance to melanoma liver metastases and enhanced natural killer cell activity

Sudha Neelam, Jessamee Mellon, Amber Wilkerson, Jerry Y. Niederkorn

Research output: Contribution to journalArticle

Abstract

The objective was to determine if the absence of FasL signaling would affect melanoma liver metastases by influencing the antimelanoma properties of liver natural killer (NK) cells. Melanoma liver metastases were induced in wild-type C57BL/6 mice and the gld/gld mutant C57BL/6 mouse strain that expresses a defective form of FasL (CD95L) that fails to engage and signal via the Fas receptor (CD95). Liver metastases were produced by intrasplenic injection of B16LS9 melanoma cells. Liver NK cell activity directed against murine B16LS9 melanoma cells was determined in a 24 h in-vitro cytotoxicity assay. Liver NK cells, NK T cells, and the NK cell surface activation marker, NKG2D, were measured by flow cytometry. Mice expressing defective FasL displayed reduced, rather than enhanced, melanoma liver metastases that coincided with increased liver NK cell-mediated tumor cell cytotoxicity. Enhanced cytotoxicity was not mediated by perforin, tumor necrosis factor-α, or tumor necrosis-associated apoptosis-inducing ligand but was closely associated with elevated interferon-γ in the tumor-bearing liver. FasL-defective gld/gld mice also displayed reduced numbers of liver NK T cells, which have been previously implicated in suppression on liver NK cell activity. The absence of functional FasL in the liver correlates with a heightened, not diminished, resistance to melanoma liver metastases. The resistance to liver metastases coincides with a significant, albeit transient, increase in liver NK cytotoxicity and elevated levels of interferon-γ in the liver.

Original languageEnglish (US)
Pages (from-to)401-412
Number of pages12
JournalMelanoma research
Volume29
Issue number4
DOIs
Publication statusPublished - Aug 1 2019

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ASJC Scopus subject areas

  • Oncology
  • Dermatology
  • Cancer Research

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