Melanoma Cells Control Antimelanoma CTL Responses via Interaction between TIGIT and CD155 in the Effector Phase

J Invest Dermatol. 2016 Jan;136(1):255-63. doi: 10.1038/JID.2015.404.


Recently, T-cell immunoreceptor with Ig and ITIM domains (TIGIT) was reported as a candidate for novel immune checkpoints. However, the impact of TIGIT on melanoma-specific cytotoxic T lymphocytes in the effector phase remains unclear. In this study, we demonstrated that melanoma cells control antimelanoma cytotoxic T lymphocyte responses via the TIGIT-CD155 interaction in the effector phase. TIGIT is an inhibitory receptor expressed on T cells, and CD155 is one of the cognate ligands expressed on the tumor cells or antigen-presenting cells. First, we confirmed that CD155 was constitutively expressed on melanoma cells. We then demonstrated that CD155 on melanoma cells suppressed cytokine release from melanoma-specific cytotoxic T lymphocytes via interaction with TIGIT. Overexpression of CD155 enhanced and its downregulation attenuated the suppressive effect. This suggested that antimelanoma cytotoxic T lymphocyte responses are controlled not only by an imbalance in CD226 (an activating molecule that binds to CD155) and TIGIT expression on T cells but also by the expression levels of CD155 on melanoma cells. In addition, the co-blockade of TIGIT and PD-1 signals synergistically elicited a response of tumor-infiltrating lymphocytes on autologous melanoma cells. These results suggest that the CD155-TIGIT interaction should be blocked for enhancement of antimelanoma immune responses.

MeSH terms

  • Antigen-Presenting Cells / immunology
  • Antigens, CD / metabolism
  • Antigens, Neoplasm / metabolism
  • Antigens, Surface / metabolism
  • Biomarkers, Tumor / metabolism*
  • Cytokines / immunology
  • Cytokines / metabolism
  • Humans
  • Immunohistochemistry
  • Lymphocyte Activation / immunology
  • Melanoma / immunology
  • Melanoma / pathology
  • Organic Cation Transport Proteins / metabolism
  • RNA, Small Interfering / immunology
  • RNA, Small Interfering / metabolism*
  • Receptors, Immunologic / metabolism*
  • Receptors, Virus / metabolism*
  • Skin Neoplasms / immunology
  • Skin Neoplasms / pathology
  • T-Lymphocytes, Cytotoxic / immunology
  • Tumor Cells, Cultured


  • Antigens, CD
  • Antigens, Neoplasm
  • Antigens, Surface
  • Biomarkers, Tumor
  • CTAG2 protein, human
  • Cytokines
  • Organic Cation Transport Proteins
  • RNA, Small Interfering
  • Receptors, Immunologic
  • Receptors, Virus
  • SLC44A1 protein, human
  • TIGIT protein, human
  • poliovirus receptor