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Measurement of Natural Killer Cell-Mediated Cytotoxicity and Migration in the Context of Hepatic Tumor Cells
Published on: February 22, 2020
Tumor-derived soluble CD155 inhibits DNAM-1-mediated antitumor activity of natural killer cells
Genki Okumura1,2, Akiko Iguchi-Manaka3, Rikito Murata1,4
1Department of Immunology, University of Tsukuba, Tsukuba, Ibaraki, Japan.
Abstract:
CD155 is a ligand for DNAM-1, TIGIT, and CD96 and is involved in tumor immune responses. Unlike mouse cells, human cells express both membranous CD155 and soluble CD155 (sCD155) encoded by splicing isoforms of CD155. However, the role of sCD155 in tumor immunity remains unclear. Here, we show that, after intravenous injection with sCD155-producing B16/BL6 melanoma, the numbers of tumor colonies in wild-type (WT), TIGIT knock-out (KO), or CD96 KO mice, but not DNAM-1 KO mice, were greater than after injection with parental B16/BL6 melanoma. NK cell depletion canceled the difference in the numbers of tumor colonies in WT mice. In vitro assays showed that sCD155 interfered with DNAM-1-mediated NK cell degranulation. In addition, DNAM-1 had greater affinity than TIGIT and CD96 for sCD155, suggesting that sCD155 bound preferentially to DNAM-1. Together, these results demonstrate that sCD155 inhibits DNAM-1-mediated cytotoxic activity of NK cells, thus promoting the lung colonization of B16/BL6 melanoma.
Insights
Soluble CD155 (sCD155) promotes melanoma lung colonization by inhibiting DNAM-1-mediated natural killer (NK) cell activity. This soluble form of CD155 hinders NK cell degranulation, impacting tumor immune responses.
Area of Science:
- Immunology
- Cancer Biology
- Molecular Biology
Background:
- CD155 is a key ligand in tumor immunity, interacting with DNAM-1, TIGIT, and CD96.
- Human cells express both membrane-bound and soluble CD155 (sCD155), unlike mouse cells.
- The specific role of sCD155 in tumor immunity is not well understood.
Purpose of the Study:
- To investigate the function of sCD155 in the context of tumor immune responses.
- To determine the impact of sCD155 on melanoma lung colonization and natural killer (NK) cell activity.
Main Methods:
- Intravenous injection of sCD155-producing B16/BL6 melanoma cells into wild-type and knockout mice.
- NK cell depletion experiments in wild-type mice.
- In vitro assays to assess NK cell degranulation and binding affinities of sCD155 to DNAM-1, TIGIT, and CD96.
Main Results:
- sCD155-producing melanoma increased tumor colonies in wild-type, TIGIT KO, and CD96 KO mice, but not in DNAM-1 KO mice.
- NK cell depletion abrogated the increased tumor colonization observed in wild-type mice.
- In vitro, sCD155 inhibited DNAM-1-mediated NK cell degranulation and showed preferential binding to DNAM-1 over TIGIT and CD96.
Conclusions:
- sCD155 actively suppresses DNAM-1-mediated cytotoxic activity of NK cells.
- This suppression by sCD155 promotes the lung colonization of B16/BL6 melanoma.
- Soluble CD155 represents a novel mechanism by which tumors can evade NK cell-mediated immune surveillance.
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