Taste receptor T1R1/T1R3 promotes the tumoricidal activity of hepatic CD49a+ CD49b- natural killer cells

Eur J Immunol. 2018 Dec;48(12):2031-2041. doi: 10.1002/eji.201847688. Epub 2018 Oct 10.

Abstract

Natural Killer (NK) cell-based immunotherapy is a promising approach to treat hepatocellular carcinoma (HCC). The mechanisms underlying the regulation of NK cell activity are not completely understood. In this research, we identified the expression of taste receptor type 1 member 1 (T1R1) and taste receptor type 1 member 3 (T1R3) in a subset of hepatic NK cells in a mouse HCC model. T1R1 and T1R3 were selectively expressed in CD49a+ CD49b- NK cells in livers with HCC. In the in vitro cytotoxicity assay, amino acids promoted the tumoricidal effect of CD49a+ CD49b- NK cells through increasing the production of perforin, granzyme B and IFN-γ. Furthermore, using a lentivirus to induce the expression of exogenous T1R1 and T1R3 in normal hepatic NK cells, we found that amino acids enhanced NK cell-mediated cytotoxicity on tumor cells through the T1R1/T1R3 receptor, as demonstrated by more tumor cell lysis, up-regulation of perforin and granzyme B in comparison with control NK cells. In addition, amino acids activated Akt and mechanistic target of rapamycin complex 1 (mTORC1) signaling in NK cells through T1R1/T1R3 receptor. T-bet expression in NK cells was also increased by amino acid treatment. Therefore, T1R1/T1R3 receptor promotes the tumoricidal activity of hepatic CD49a+ CD49b- NK cells.

Keywords: Anti-tumor immunity; Cancer immunotherapy; Hepatocellular carcinoma; Natural Killer (NK) cells; Taste receptor T1R1/T1R3.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / metabolism
  • Animals
  • Carbon Tetrachloride
  • Carcinoma, Hepatocellular / immunology*
  • Carcinoma, Hepatocellular / therapy
  • Cells, Cultured
  • Cytotoxicity, Immunologic
  • Disease Models, Animal
  • Humans
  • Immunotherapy, Adoptive / methods*
  • Integrin alpha1 / metabolism
  • Integrin alpha2 / metabolism
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / transplantation
  • Liver / immunology*
  • Liver Neoplasms / immunology*
  • Liver Neoplasms / therapy
  • Male
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Oncogene Protein v-akt / metabolism
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*
  • Signal Transduction
  • T-Box Domain Proteins / genetics
  • T-Box Domain Proteins / metabolism

Substances

  • Amino Acids
  • Integrin alpha1
  • Integrin alpha2
  • Receptors, G-Protein-Coupled
  • T-Box Domain Proteins
  • T-box transcription factor TBX21
  • taste receptors, type 1
  • Carbon Tetrachloride
  • Mechanistic Target of Rapamycin Complex 1
  • Oncogene Protein v-akt