Sulforaphane enhances the antitumor response of chimeric antigen receptor T cells by regulating PD-1/PD-L1 pathway
| Autor: | Lingxiao Zhou, Wenyi Jiang, Yonggui Tian, Zhen Zhang, Chunyi Shen, Liping Wang, Feng Li, Yi Zhang, Li Yang, Bin Zhang |
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| Rok vydání: | 2021 |
| Předmět: |
T-Lymphocytes
medicine.medical_treatment Programmed Cell Death 1 Receptor B7-H1 Antigen Proinflammatory cytokine Cell therapy Mice Immune system Cancer immunotherapy Isothiocyanates In vivo Cell Line Tumor PD-L1 medicine Animals Humans Programmed cell death 1 Antitumor response Cytotoxicity Programmed cell death ligand 1 Receptors Chimeric Antigen biology business.industry Chimeric antigen receptor T cells Immunity General Medicine Xenograft Model Antitumor Assays Chimeric antigen receptor Sulfoxides Cancer research biology.protein Medicine business Sulforaphane Research Article |
| Zdroj: | BMC Medicine BMC Medicine, Vol 19, Iss 1, Pp 1-16 (2021) |
| ISSN: | 1741-7015 |
| DOI: | 10.1186/s12916-021-02161-8 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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