Sulforaphane enhances the antitumor response of chimeric antigen receptor T cells by regulating PD-1/PD-L1 pathway

Chunyi Shen, Zhen Zhang, Yonggui Tian, Feng Li, Lingxiao Zhou, Wenyi Jiang, Li Yang, Bin Zhang, Liping Wang*, Yi Zhang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

Background: Chimeric antigen receptor T (CAR-T) cell therapy has limited effects in the treatment of solid tumors. Sulforaphane (SFN) is known to play an important role in inhibiting tumor growth, but its effect on CAR-T cells remains unclear. The goal of the current study was to determine whether combined CAR-T cells and SFN could provide antitumor efficacy against solid tumors. Methods: The effect of combined SFN and CAR-T cells was determined in vitro using a co-culture system and in vivo using a xenograft mouse model. We further validated the effects of combination therapy in patients with cancer. Results: In vitro, the combination of SFN and CAR-T cells resulted in enhanced cytotoxicity and increased lysis of tumor cells. We found that SFN suppressed programmed cell death 1 (PD-1) expression in CAR-T cells and potentiated antitumor functions in vitro and in vivo. As a ligand of PD-1, programmed cell death ligand 1 (PD-L1) expression was also decreased in tumor cells after SFN treatment. In addition, β-TrCP was increased by SFN, resulting in higher activation of ubiquitination-mediated proteolysis of PD-L1, which induced PD-L1 degradation. The combination of SFN and CAR-T cell therapy acted synergistically to promote better immune responses in vivo compared with monotherapy. In clinical treatments, PD-1 expression was lower, and proinflammatory cytokine levels were higher in patients with various cancers who received CAR-T cells and took SFN orally than that in the control group. Conclusion: SFN improves the cytotoxicity of CAR-T cells by modulating the PD-1/PD-L1 pathway, which may provide a promising strategy for the combination of SFN with CAR-T cells for cancer immunotherapy.

Original languageEnglish (US)
Article number283
JournalBMC Medicine
Volume19
Issue number1
DOIs
StatePublished - Dec 2021

Keywords

  • Antitumor response
  • Chimeric antigen receptor T cells
  • Programmed cell death 1
  • Programmed cell death ligand 1
  • Sulforaphane

ASJC Scopus subject areas

  • General Medicine

Fingerprint

Dive into the research topics of 'Sulforaphane enhances the antitumor response of chimeric antigen receptor T cells by regulating PD-1/PD-L1 pathway'. Together they form a unique fingerprint.

Cite this