Restricting Glycolysis Preserves T Cell Effector Functions and Augments Checkpoint Therapy

Area of Science:

• Oncology
• Immunology
• Pharmacology

Background:

• Tumor-derived lactic acid suppresses T-cell and NK-cell function, hindering anti-tumor immunity.
• High expression of glycolysis genes in melanoma correlates with poor progression-free survival during anti-PD1 therapy.

Purpose of the Study:

• To investigate the role of tumor glycolysis in anti-PD1 therapy response.
• To evaluate the potential of targeting tumor lactate secretion with diclofenac to enhance checkpoint inhibitor efficacy.

Main Methods:

• In vitro assessment of diclofenac's effect on tumor cell lactate secretion and T-cell killing.
• In vitro analysis of T-cell function under diclofenac treatment and low glucose conditions.
• In vivo studies evaluating diclofenac's impact on tumor growth and checkpoint therapy efficacy.
• Genetic suppression of tumor glycolysis to assess its effect on checkpoint therapy.

Main Results:

• Diclofenac inhibits monocarboxylate transporters 1 and 4, reducing lactate efflux from tumor cells.
• Diclofenac treatment preserves T-cell activation, viability, and effector functions in vitro.
• Diclofenac delays tumor growth and enhances anti-PD1 therapy in vivo, unlike aspirin.
• Genetic reduction of tumor glycolysis significantly improves checkpoint therapy outcomes.

Conclusions:

• Tumor glycolysis is a key mechanism limiting checkpoint inhibitor efficacy.
• Diclofenac's inhibition of lactate transport represents a promising strategy to overcome resistance to anti-PD1 therapy.
• Targeting tumor glycolysis in combination with checkpoint inhibitors warrants clinical investigation for melanoma patients with high glycolytic tumors.