Combination of IL-21 and IL-15 enhances tumour-specific cytotoxicity and cytokine production of TCR-transduced primary T cells

Cancer Immunol Immunother. 2010 Jun;59(6):921-31. doi: 10.1007/s00262-010-0818-0. Epub 2010 Jan 26.

Abstract

IL-21, and to a lesser extent IL-15, inhibits differentiation of antigen-primed CD8 T cells and promotes their homeostasis and anti-tumour activity. Here, we investigated molecular mechanisms behind tumour-specific responses of primary murine T lymphocytes engineered to express a TCR directed against human gp100/HLA-A2 following short-term exposure to IL-15 and/or IL-21. We demonstrated that IL-15 + IL-21, and to a lesser extent IL-21, enhanced antigen-specific T-cell cytotoxicity, which was related to enhanced expression of granzymes A and B, and perforin 1. Furthermore, IL-15 + IL-21 synergistically enhanced release levels and kinetics of T-cell IFNgamma and IL-2, but not IL-10. Enhanced secretion of IFNgamma was accompanied by increased gene expression and cytosolic protein content, and was restricted to effector memory T cells. To summarize, we show that IL-15 + IL-21 improves antigen-specific responses of TCR-transduced effector T cells at multiple levels, which provides a rationale to treat T cells with a combination of these cytokines prior to their use in adoptive TCR gene therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Neoplasm / immunology
  • CD8-Positive T-Lymphocytes / drug effects*
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / pathology
  • Cell Line, Tumor
  • Cytokines / genetics
  • Cytokines / metabolism
  • Cytotoxicity, Immunologic / drug effects
  • Cytotoxicity, Immunologic / immunology
  • Drug Synergism
  • Granzymes / biosynthesis
  • Granzymes / genetics
  • HLA-A2 Antigen / immunology
  • Humans
  • Immunologic Memory
  • Immunotherapy, Adoptive*
  • Interleukin-15 / pharmacology*
  • Interleukin-21
  • Interleukins / pharmacology*
  • Melanoma / immunology
  • Melanoma / metabolism
  • Melanoma / pathology
  • Melanoma / therapy*
  • Membrane Glycoproteins / immunology
  • Mice
  • Perforin / biosynthesis
  • Perforin / genetics
  • Protein Engineering
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / immunology
  • Receptors, Antigen, T-Cell / metabolism
  • Transduction, Genetic
  • gp100 Melanoma Antigen

Substances

  • Antigens, Neoplasm
  • Cytokines
  • HLA-A2 Antigen
  • Interleukin-15
  • Interleukins
  • Membrane Glycoproteins
  • PMEL protein, human
  • Pmel protein, mouse
  • Receptors, Antigen, T-Cell
  • gp100 Melanoma Antigen
  • Perforin
  • Granzymes
  • Interleukin-21