Curcumin analog GO-Y030 boosts the efficacy of anti-PD-1 cancer immunotherapy

Takashi MaruYama, Shuhei Kobayashi, Hiroyuki Shibata, Wan Jun Chen, Yuji Owada

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)

Abstract

Regulatory T cells (Tregs) in the tumor microenvironment regulate tumor immunity. Programmed cell death protein 1 (PD-1) is known to be expressed on Tregs and plays crucial roles in suppressing tumor immunity. However, the immune checkpoint inhibitor, anti-PD-1 antibody, is known to promote the proliferation of the Treg population in tumor-infiltrating lymphocytes, thereby restricting the efficacy of cancer immunotherapy. In this study, we focused on the curcumin analog GO-Y030, an antitumor chemical. GO-Y030 inhibited the immune-suppressive ability of Tregs via metabolic changes in vitro, even in the presence of immune checkpoint inhibitors. Mechanistically, GO-Y030 inhibited the mTOR-S6 axis in Tregs, which plays a pivotal role in their immune-suppressive ability. GO-Y030 also controlled the metabolism in cultured CD4+ T cells in the presence of TGF-β + IL-6; however, it did not prevent Th17 differentiation. Notably, GO-Y030 significantly inhibited IL-10 production from Th17 cells. In the tumor microenvironment, L-lactate produced by tumors is known to support the suppressive ability of Tregs, and GO-Y030 treatment inhibited L-lactate production via metabolic changes. In addition, experiments in the B16-F10 melanoma mouse model revealed that GO-Y030 helped inhibit the anti-PD-1 immune checkpoint and reduce the Treg population in tumor-infiltrating lymphocytes. Thus, GO-Y030 controls the metabolism of both Tregs and tumors and could serve as a booster for anti-immune checkpoint inhibitors.

Original languageEnglish
Pages (from-to)4844-4852
Number of pages9
JournalCancer Science
Volume112
Issue number12
DOIs
Publication statusPublished - 2021 Dec

Keywords

  • GO-Y030
  • cancer immunotherapy
  • metabolism
  • programmed cell death protein 1
  • regulatory T cells

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