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L-5-hydroxytryptophan promotes antitumor immunity by inhibiting PD-L1 inducible expression

文献类型：期刊论文

作者Huang, Jing5,6; Wang, Xiaobo4; Li, Bing5,6; Shen, Shiyu3; Wang, Ruina4; Tao, Hongru2,6; Hu, Junchi; Yu, Jin3; Jiang, Hualiang5,6; Chen, Kaixian5,6
刊名JOURNAL FOR IMMUNOTHERAPY OF CANCER
出版日期2022-06-01
卷号10期号:6页码:14
关键词Immunotherapy Immune Evation T-Lymphocytes Translational Medical Research
DOI10.1136/jitc-2021-003957
通讯作者Luo, Cheng(cluo@simm.ac.cn) ; Dang, Yongjun(yjdang@cqmu.edu) ; Zhang, Yuanyuan(zhangyy@simm.ac.cn)
英文摘要Background The repression or downregulation of programmed death-ligand 1 (PD-L1) can release its inhibition of T cells and activate antitumor immune responses. Although PD-1 and PD-L1 antibodies are promising treatments for diverse tumor types, their inherent disadvantages and immune-related adverse events remain significant issues. The development of small molecule inhibitors targeting the interaction surface of PD-1 and PD-L1 has been reviving, yet many challenges remain. To address these issues, we aimed to find small molecules with durable efficacy and favorable biosafety that alter PD-L1 surface expression and can be developed into a promising alternative and complementary therapy for existing anti-PD-1/PD-L1 therapies. Methods Cell-based screen of 200 metabolic molecules using a high-throughput flow cytometry assay of PD-L1 surface expression was conducted, and L-5-hydroxytryptophan (L-5-HTP) was found to suppress PD-L1 expression induced by interferon gamma (IFN-gamma). Inhibition of PD-L1 induction and antitumor effect of L-5-HTP were evaluated in two syngeneic mouse tumor models. Flow cytometry was performed to investigate the change in the tumor microenvironment caused by L-5-HTP treatment. Results We discovered that L-5-HTP suppressed IFN-gamma-induced PD-L1 expression in tumor cells transcriptionally, and this effect was directly due to itself. Mechanistically, L-5-HTP inhibited IFN-gamma-induced expression of RTK ligands and thus suppressed phosphorylation-mediated activation of RTK receptors and the downstream MEK/ERK/c-JUN signaling cascade, leading to decreased PD-L1 induction. In syngeneic mouse tumor models, treatment with 100 mg/kg L-5-HTP (intraperitoneal) inhibited PD-L1 expression and exhibited antitumor effect. L-5-HTP upregulated the ratio of granzyme B+ CD8+ activated cytotoxic T cells. An intact immune system and PD-L1 expression was critical for L-5-HTP to exert its antitumor effects. Furthermore, L-5-HTP acted synergistically with PD-1 antibody to improve anticancer effect. Conclusion Our study illustrated L-5-HTP's inhibitory effect on PD-L1 induction stimulated by IFN-gamma in tumor cells and also provided insight into repurposing L-5-HTP for use in tumor immunotherapy.
WOS关键词MONOCLONAL-ANTIBODIES ; B7-H1 ; 5-HYDROXYTRYPTOPHAN ; SUPPLEMENTATION ; DEPRESSION ; BIOLOGY ; MEMBER ; MEK
资助项目National Key Research and Development Program of China[2021ZD0203900] ; National Natural Science Foundation of China[81803554] ; National Natural Science Foundation of China[81625022] ; National Natural Science Foundation of China[81821005] ; National Natural Science Foundation of China[91853205] ; National Natural Science Foundation of China[21820102008] ; Science and Technology Commission of Shanghai Municipality[18431907100] ; Science and Technology Commission of Shanghai Municipality[19XD1404700] ; National Multidisciplinary Innovation Team of Traditional Chinese Medicine - National Administration of Traditional Chinese Medicine[ZYYCXTD-202004] ; Lingang Laboratory[LG-QS-202206-01]
WOS研究方向Oncology ; Immunology
语种英语
出版者BMJ PUBLISHING GROUP
WOS记录号WOS:000815215400008
源URL[http://119.78.100.183/handle/2S10ELR8/301629]  
专题新药研究国家重点实验室
通讯作者Luo, Cheng; Dang, Yongjun; Zhang, Yuanyuan
作者单位1.Chongqing Med Univ, Ctr Novel Target & Therapeut Intervent, Chongqing, Peoples R China
2.Harbin Inst Technol, Sch Life Sci & Technol, Harbin, Peoples R China
3.Fudan Univ, Shanghai Med Coll, Brain Sci Collaborat Innovat Ctr,State Key Lab Me, Inst Brain Sci,Sch Basic Med Sci,Dept Integrat Me, Shanghai, Peoples R China
4.Fudan Univ, Sch Basic Med Sci, Dept Biochem & Mol Biol, Key Lab Metab & Mol Med,Minist Educ, Shanghai, Peoples R China
5.Univ Chinese Acad Sci, Beijing, Peoples R China
6.Chinese Acad Sci, Drug Discovery & Design Ctr, Ctr Chem Biol, State Key Lab Drug Res,Shanghai Inst Mat Med, Shanghai, Peoples R China
推荐引用方式
GB/T 7714		 Huang, Jing,Wang, Xiaobo,Li, Bing,et al. L-5-hydroxytryptophan promotes antitumor immunity by inhibiting PD-L1 inducible expression[J]. JOURNAL FOR IMMUNOTHERAPY OF CANCER,2022,10(6):14.
APA Huang, Jing.,Wang, Xiaobo.,Li, Bing.,Shen, Shiyu.,Wang, Ruina.,...&Zhang, Yuanyuan.(2022).L-5-hydroxytryptophan promotes antitumor immunity by inhibiting PD-L1 inducible expression.JOURNAL FOR IMMUNOTHERAPY OF CANCER,10(6),14.
MLA Huang, Jing,et al."L-5-hydroxytryptophan promotes antitumor immunity by inhibiting PD-L1 inducible expression".JOURNAL FOR IMMUNOTHERAPY OF CANCER 10.6(2022):14.

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来源：上海药物研究所

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