Resveratrol reduces lactate production and modifies the ovarian cancer immune microenvironment

Neoplasma. 2022 Sep;69(5):1129-1137. doi: 10.4149/neo_2022_220414N410. Epub 2022 Sep 22.

Abstract

Tumor cells show deregulated metabolism leading to an enrichment of lactate in the tumor microenvironment (TME). This lactate-rich environment has been reported to impair effector T cells. However, T-regulatory cells (Tregs) show metabolic advantages in lactate-rich TME that maintain a strong suppression of effector T cells, which leads to tumor immune evasion. Therefore, the glycolytic process of tumors could represent a therapeutic target, and agents that modify the energy metabolism of tumor cells have therapeutic potential. Resveratrol is a naturally occurring polyphenol that has been confirmed to suppress tumor cells' glycolytic metabolism. In this study, we show that resveratrol induces metabolic reprogramming in ovarian cancer cells. Resveratrol increases oxidative and decreases glycolysis, in association with decreased lactate production both in vitro and in vivo. Lactate reduction in TME weakens the suppressive function of Tregs, and subsequently restores anti-tumor immunity. Significantly, combined resveratrol and PD-1 blockade promote anti-tumor efficacy. These data suggest that resveratrol's anti-tumor actions in ovarian cancer could be explained, in part, through modification of the anti-tumor immunity, and indicate a novel treatment strategy for improving immune checkpoint blockade therapy using resveratrol.

MeSH terms

  • Carcinoma, Ovarian Epithelial
  • Female
  • Humans
  • Immune Checkpoint Inhibitors
  • Lactic Acid
  • Neoplasms* / drug therapy
  • Ovarian Neoplasms* / pathology
  • Polyphenols
  • Programmed Cell Death 1 Receptor
  • Resveratrol / pharmacology
  • Tumor Microenvironment

Substances

  • Immune Checkpoint Inhibitors
  • Polyphenols
  • Programmed Cell Death 1 Receptor
  • Lactic Acid
  • Resveratrol