Augmented anti-tumor activity of NK-92 cells expressing chimeric receptors of TGF-βR II and NKG2D

Cancer Immunol Immunother. 2017 Apr;66(4):537-548. doi: 10.1007/s00262-017-1959-1. Epub 2017 Feb 9.

Abstract

The capacity of natural killer (NK) cells to kill tumor cells without specific antigen recognition provides an advantage over T cells and makes them potential effectors for tumor immunotherapy. However, the efficacy of NK cell adoptive therapy can be limited by the immunosuppressive tumor microenvironment. Transforming growth factor-β (TGF-β) is a potent immunosuppressive cytokine that can suppress NK cell function. To convert the suppressive signal induced by TGF-β to an activating signal, we genetically modified NK-92 cells to express a chimeric receptor with TGF-β type II receptor extracellular and transmembrane domains and the intracellular domain of NK cell-activating receptor NKG2D (TN chimeric receptor). NK-92 cells expressing TN receptors were resistant to TGF-β-induced suppressive signaling and did not down-regulate NKG2D. These modified NK-92 cells had higher killing capacity and interferon γ (IFN-γ) production against tumor cells compared with the control cells and their cytotoxicity could be further enhanced by TGF-β. More interestingly, the NK-92 cells expressing TN receptors were better chemo-attracted to the tumor cells expressing TGF-β. The presence of these modified NK-92 cells significantly inhibited the differentiation of human naïve CD4+ T cells to regulatory T cells. NK-92-TN cells could also inhibit tumor growth in vivo in a hepatocellular carcinoma xenograft tumor model. Therefore, TN chimeric receptors can be a novel strategy to augment anti-tumor efficacy in NK cell adoptive therapy.

Keywords: Chimeric receptor; Immunotherapy; NK-92 cell; NKG2D; TGF-βR II.

MeSH terms

  • Animals
  • Cancer Vaccines / immunology*
  • Carcinoma, Hepatocellular / immunology
  • Carcinoma, Hepatocellular / therapy*
  • Cell Differentiation
  • Cell Growth Processes
  • Cell Line, Tumor
  • Cell Movement
  • Cytotoxicity, Immunologic
  • Humans
  • Immunotherapy, Adoptive / methods*
  • Interferon-gamma / metabolism
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / transplantation
  • Liver Neoplasms / immunology
  • Liver Neoplasms / therapy*
  • Mice
  • Mice, Nude
  • NK Cell Lectin-Like Receptor Subfamily K / genetics
  • NK Cell Lectin-Like Receptor Subfamily K / metabolism*
  • Neoplasms, Experimental
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / genetics
  • Receptors, Transforming Growth Factor beta / metabolism*
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism*
  • T-Lymphocytes, Regulatory / immunology*
  • Transforming Growth Factor beta / metabolism
  • Tumor Microenvironment
  • Xenograft Model Antitumor Assays

Substances

  • Cancer Vaccines
  • KLRK1 protein, human
  • NK Cell Lectin-Like Receptor Subfamily K
  • Receptors, Transforming Growth Factor beta
  • Recombinant Fusion Proteins
  • Transforming Growth Factor beta
  • Interferon-gamma
  • Protein Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II