PPAR-Induced Fatty Acid Oxidation in T Cells Increases the Number of Tumor-Reactive CD8+ T Cells and Facilitates Anti-PD-1 Therapy

Cancer Immunol Res. 2018 Nov;6(11):1375-1387. doi: 10.1158/2326-6066.CIR-18-0095. Epub 2018 Aug 24.

Abstract

Although PD-1 blockade cancer immunotherapy has shown potential for a wide range of patients with cancer, its efficacy is limited, in part, due to the loss of effector cytotoxic T lymphocytes (CTLs) via terminal differentiation-induced apoptosis. We previously demonstrated that mitochondrial activation, by the agonists of peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1-α (PGC-1α)/transcription factor complexes, had synergistic effects with a PD-1-blocking monoclonal antibody in a mouse tumor model. In the current study, we examined the molecular mechanism of the synergistic effects of bezafibrate, an agonist of PGC-1α/ PPAR complexes, which enhanced the tumoricidal effects of PD-1 blockade. Bezafibrate activated CTL mitochondria and upregulated oxidative phosphorylation as well as glycolysis, resulting in more proliferation of naïve T cells and improved effector function in CTLs. Bezafibrate also increased fatty acid oxidation (FAO) and mitochondrial respiratory capacity, which supports the extra energy demands of cells in emergencies, allowing cell survival. Carnitine palmitoyl transferase 1 (Cpt1), which is needed for FAO, and Bcl2 were both upregulated. Cpt1 and Bcl2 can form a complex to prevent apoptosis of CTLs. Together, these results indicate that bezafibrate increases or maintains the number of functional CTLs by activating mitochondrial and cellular metabolism, leading in turn to enhanced antitumor immunity during PD-1 blockade. Cancer Immunol Res; 6(11); 1375-87. ©2018 AACR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / administration & dosage
  • Antibodies, Monoclonal / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Bezafibrate / administration & dosage
  • Bezafibrate / pharmacology*
  • CD8 Antigens / genetics
  • CD8-Positive T-Lymphocytes / drug effects*
  • Cell Differentiation
  • Fatty Acids / metabolism*
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Molecular Targeted Therapy / methods
  • Neoplasms, Experimental / drug therapy
  • Neoplasms, Experimental / immunology
  • Neoplasms, Experimental / pathology
  • Oxidation-Reduction
  • Oxidative Phosphorylation / drug effects
  • Peroxisome Proliferator-Activated Receptors / metabolism*
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors*
  • Programmed Cell Death 1 Receptor / immunology
  • T-Lymphocytes, Cytotoxic / drug effects
  • T-Lymphocytes, Cytotoxic / immunology
  • T-Lymphocytes, Cytotoxic / metabolism

Substances

  • Antibodies, Monoclonal
  • CD8 Antigens
  • Fatty Acids
  • Pdcd1 protein, mouse
  • Peroxisome Proliferator-Activated Receptors
  • Programmed Cell Death 1 Receptor
  • Bezafibrate