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.
Keywords: Antitumor response; Chimeric antigen receptor T cells; Programmed cell death 1; Programmed cell death ligand 1; Sulforaphane.
© 2021. The Author(s).