Increased Tumor Glycolysis Characterizes Immune Resistance to Adoptive T Cell Therapy

Cell Metab. 2018 May 1;27(5):977-987.e4. doi: 10.1016/j.cmet.2018.02.024. Epub 2018 Apr 5.


Adoptive T cell therapy (ACT) produces durable responses in some cancer patients; however, most tumors are refractory to ACT and the molecular mechanisms underlying resistance are unclear. Using two independent approaches, we identified tumor glycolysis as a pathway associated with immune resistance in melanoma. Glycolysis-related genes were upregulated in melanoma and lung cancer patient samples poorly infiltrated by T cells. Overexpression of glycolysis-related molecules impaired T cell killing of tumor cells, whereas inhibition of glycolysis enhanced T cell-mediated antitumor immunity in vitro and in vivo. Moreover, glycolysis-related gene expression was higher in melanoma tissues from ACT-refractory patients, and tumor cells derived from these patients exhibited higher glycolytic activity. We identified reduced levels of IRF1 and CXCL10 immunostimulatory molecules in highly glycolytic melanoma cells. Our findings demonstrate that tumor glycolysis is associated with the efficacy of ACT and identify the glycolysis pathway as a candidate target for combinatorial therapeutic intervention.

Keywords: adoptive T cell therapy; cancer immunotherapy; glycolysis; immune resistance; melanoma; non-small cell lung cancer; tumor metabolism reprogramming.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Chemokine CXCL10 / metabolism
  • Female
  • Glycolysis*
  • Humans
  • Immunotherapy, Adoptive*
  • Interferon Regulatory Factor-1 / metabolism
  • Lung Neoplasms / immunology
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / therapy*
  • Male
  • Melanoma / immunology
  • Melanoma / metabolism
  • Melanoma / therapy*
  • Mice
  • Mice, Inbred C57BL
  • T-Lymphocytes / transplantation*


  • CXCL10 protein, human
  • Chemokine CXCL10
  • IRF1 protein, human
  • Interferon Regulatory Factor-1