Sulforaphane enhances the antitumor response of chimeric antigen receptor T cells by regulating PD-1/PD-L1 pathway
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 w...
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2021
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oai:doaj.org-article:fa4414bc3272439a9714929ad02b26892021-11-28T12:15:24ZSulforaphane enhances the antitumor response of chimeric antigen receptor T cells by regulating PD-1/PD-L1 pathway10.1186/s12916-021-02161-81741-7015https://doaj.org/article/fa4414bc3272439a9714929ad02b26892021-11-01T00:00:00Zhttps://doi.org/10.1186/s12916-021-02161-8https://doaj.org/toc/1741-7015Abstract 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.Chunyi ShenZhen ZhangYonggui TianFeng LiLingxiao ZhouWenyi JiangLi YangBin ZhangLiping WangYi ZhangBMCarticleSulforaphaneChimeric antigen receptor T cellsProgrammed cell death 1Programmed cell death ligand 1Antitumor responseMedicineRENBMC Medicine, Vol 19, Iss 1, Pp 1-16 (2021) |
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Sulforaphane Chimeric antigen receptor T cells Programmed cell death 1 Programmed cell death ligand 1 Antitumor response Medicine R |
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Sulforaphane Chimeric antigen receptor T cells Programmed cell death 1 Programmed cell death ligand 1 Antitumor response Medicine R Chunyi Shen Zhen Zhang Yonggui Tian Feng Li Lingxiao Zhou Wenyi Jiang Li Yang Bin Zhang Liping Wang Yi Zhang Sulforaphane enhances the antitumor response of chimeric antigen receptor T cells by regulating PD-1/PD-L1 pathway |
| description |
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. |
| format |
article |
| author |
Chunyi Shen Zhen Zhang Yonggui Tian Feng Li Lingxiao Zhou Wenyi Jiang Li Yang Bin Zhang Liping Wang Yi Zhang |
| author_facet |
Chunyi Shen Zhen Zhang Yonggui Tian Feng Li Lingxiao Zhou Wenyi Jiang Li Yang Bin Zhang Liping Wang Yi Zhang |
| author_sort |
Chunyi Shen |
| title |
Sulforaphane enhances the antitumor response of chimeric antigen receptor T cells by regulating PD-1/PD-L1 pathway |
| title_short |
Sulforaphane enhances the antitumor response of chimeric antigen receptor T cells by regulating PD-1/PD-L1 pathway |
| title_full |
Sulforaphane enhances the antitumor response of chimeric antigen receptor T cells by regulating PD-1/PD-L1 pathway |
| title_fullStr |
Sulforaphane enhances the antitumor response of chimeric antigen receptor T cells by regulating PD-1/PD-L1 pathway |
| title_full_unstemmed |
Sulforaphane enhances the antitumor response of chimeric antigen receptor T cells by regulating PD-1/PD-L1 pathway |
| title_sort |
sulforaphane enhances the antitumor response of chimeric antigen receptor t cells by regulating pd-1/pd-l1 pathway |
| publisher |
BMC |
| publishDate |
2021 |
| url |
https://doaj.org/article/fa4414bc3272439a9714929ad02b2689 |
| work_keys_str_mv |
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1718408116243005440 |