Increased Tumor Glycolysis Characterizes Immune Resistance to Adoptive T Cell Therapy

Highlights

• Therapeutic resistance to ACT in cancer patients is poorly characterized

• T cell tumor trafficking and T cell cytotoxicity are impaired in glycolytic tumors

• Glycolysis inhibition enhances antitumor activity of tumor-reactive T cells

• Melanomas from ACT-refractory patients exhibit higher glycolytic activity

Summary

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.