Reinforce the antitumor activity of CD8 + T cells via glutamine restriction

Cancer Sci. 2018 Dec;109(12):3737-3750. doi: 10.1111/cas.13827. Epub 2018 Nov 2.

Abstract

The antitumor activity of activated CD8+ T cells in the tumor microenvironment seems to be limited due to their being metabolically unfit. This metabolic unfitness is closely associated with T-cell exhaustion and impairment of memory formation, which are barriers to successful antitumor adoptive immunotherapy. We therefore assessed the role of glutamine metabolism in the antitumor activity of CD8+ T cells using a tumor-inoculated mouse model. The adoptive transfer of tumor-specific CD8+ T cells cultured under glutamine-restricted (dGln) conditions or CD8+ T cells treated with specific inhibitors of glutamine metabolism efficiently eliminated tumors and led to better survival of tumor-inoculated mice than with cells cultured under control (Ctrl) conditions. The decreased expression of PD-1 and increased Ki67 positivity among tumor-infiltrating CD8+ T cells cultured under dGln conditions suggested that the inhibition of glutamine metabolism prevents CD8+ T-cell exhaustion in vivo. Furthermore, the transferred CD8+ T cells cultured under dGln conditions expanded more efficiently against secondary OVA stimulation than did CD8+ T cells under Ctrl conditions. We found that the expression of a pro-survival factor and memory T cell-related transcription factors was significantly higher in CD8+ T cells cultured under dGln conditions than in those cultured under Ctrl conditions. Given these findings, our study uncovered an important role of glutamine metabolism in the antitumor activity of CD8+ T cells. The novel adoptive transfer of tumor-specific CD8+ T cells cultured in glutamine-restricted conditions may be a promising approach to improve the efficacy of cell-based adoptive immunotherapy.

Keywords: CD8+ T cells; T cell memory; adoptive immunotherapy; antitumor; glutaminnolysis.

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / transplantation*
  • Cell Culture Techniques
  • Cell Line, Tumor
  • Culture Media / chemistry
  • Glutamine / deficiency*
  • Humans
  • Immunotherapy, Adoptive / methods
  • Mice
  • Thymoma / immunology
  • Thymoma / metabolism
  • Thymoma / therapy*
  • Thymus Neoplasms / immunology
  • Thymus Neoplasms / metabolism
  • Thymus Neoplasms / therapy*
  • Tumor Microenvironment
  • Xenograft Model Antitumor Assays

Substances

  • Culture Media
  • Glutamine