Increased Tumor Glycolysis Characterizes Immune Resistance to Adoptive T Cell Therapy

Abstract

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.

Sculpting tumor microenvironment with immune system: from immunometabolism to immunoediting

“…Thus, as a result of elevated glucose consumption in tumor cells, the TME becomes a glucose-deprived microenvironment in some tumor types [32][33][34]. Although the efficiency of ATP production of aerobic glycolysis is lower than oxidative phosphorylation (OXPHOS), increased glucose uptake and consumption compensate the inefficient ATP production rates and the engagement of aerobic glycolysis supports the biosynthesis of macromolecules used for cell proliferation.…”

“…Although the efficiency of ATP production of aerobic glycolysis is lower than oxidative phosphorylation (OXPHOS), increased glucose uptake and consumption compensate the inefficient ATP production rates and the engagement of aerobic glycolysis supports the biosynthesis of macromolecules used for cell proliferation. Thus, as a result of elevated glucose consumption in tumor cells, the TME becomes a glucose-deprived microenvironment in some tumor types [32][33][34]. However, metabolic reprogramming from OXPHOS to aerobic glycolysis is also required for the metabolic demands of T cell proliferation and effector functions [35].…”

Immune biomarkers for predicting response to adoptive cell transfer as cancer treatment

“…Upregulation of glycolysis pathway genes was linked to decreased T cell attraction through CXCL10, less tumour infiltration, and an impaired CTL effector phenotype in melanoma and NSCLC (Cascone et al 2018). Glycolysis pathway gene expression and the presence of lactic acid in the TME are promising biomarkers for ACT.…”

“…Because melanoma tumours which were not responsive to ACT showed upregulation of glycolytic activity, and lactic acid inhibits TIL activity in a dose-dependant manner. Luckily, lactic acid inhibitors could restore the effector phenotype of CTLs (Cascone et al 2018). …”

“…Other promising biomarkers for ACT are increased glycolysis pathway gene expression and lactic acid in the TME, which both seem to down regulate immune responses (Cascone et al 2018). At the moment, it is not yet known whether T cell priming by DCs in tumour-draining lymph nodes forms a bottleneck for treatment response to ACT.…”