Abstract
BackgroundChimeric 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.MethodsThe 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.ResultsIn 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.ConclusionSFN 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.
Highlights
Chimeric antigen receptor T (CAR-T) cell therapy has limited effects in the treatment of solid tumors
Our results showed that meso CAR-T cells had a more potent cytotoxic function against tumor cells with addition of SFN (Fig. 1C) and expressed higher levels of CD107a as an indicator of degranulation (Fig. 1D)
We tested the effect of SFN on Programmed cell death 1 (PD-1) expression and found that PD-1 was significantly inhibited by SFN in meso CAR-T cells (Fig. 1H, I, Additional file 3: Fig. S1A)
Summary
Chimeric antigen receptor T (CAR-T) cell therapy has limited effects in the treatment of solid tumors. The goal of the current study was to determine whether combined CAR-T cells and SFN could provide antitumor efficacy against solid tumors. Patients with solid tumors hardly benefit from CAR-T cell infusion due to several causes, including T cell exhaustion and tumor immune evasion in the tumor microenvironment [2,3,4]. PD-L1 expression on tumor cell surfaces leads to immune escape and poor prognosis [9]. T cells lose their effector functions and tumor cells escape from the attack. This evidence establishes a foundation for therapies that target the PD-1/PD-L1 pathway when combined with CAR-T cells. Whether there is any other safer and more effective drug combination with CAR-T therapies needs to be investigated
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