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L-5-hydroxytryptophan promotes antitumor immunity by inhibiting PD-L1 inducible expression
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 advers...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BMJ Publishing Group
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9214382/ https://www.ncbi.nlm.nih.gov/pubmed/35728870 http://dx.doi.org/10.1136/jitc-2021-003957 |
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author | Huang, Jing Wang, Xiaobo Li, Bing Shen, Shiyu Wang, Ruina Tao, Hongru Hu, Junchi Yu, Jin Jiang, Hualiang Chen, Kaixian Luo, Cheng Dang, Yongjun Zhang, Yuanyuan |
author_facet | Huang, Jing Wang, Xiaobo Li, Bing Shen, Shiyu Wang, Ruina Tao, Hongru Hu, Junchi Yu, Jin Jiang, Hualiang Chen, Kaixian Luo, Cheng Dang, Yongjun Zhang, Yuanyuan |
author_sort | Huang, Jing |
collection | PubMed |
description | 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-γ). 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-γ-induced PD-L1 expression in tumor cells transcriptionally, and this effect was directly due to itself. Mechanistically, L-5-HTP inhibited IFN-γ-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-γ in tumor cells and also provided insight into repurposing L-5-HTP for use in tumor immunotherapy. |
format | Online Article Text |
id | pubmed-9214382 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | BMJ Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-92143822022-07-07 L-5-hydroxytryptophan promotes antitumor immunity by inhibiting PD-L1 inducible expression Huang, Jing Wang, Xiaobo Li, Bing Shen, Shiyu Wang, Ruina Tao, Hongru Hu, Junchi Yu, Jin Jiang, Hualiang Chen, Kaixian Luo, Cheng Dang, Yongjun Zhang, Yuanyuan J Immunother Cancer Clinical/Translational Cancer Immunotherapy 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-γ). 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-γ-induced PD-L1 expression in tumor cells transcriptionally, and this effect was directly due to itself. Mechanistically, L-5-HTP inhibited IFN-γ-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-γ in tumor cells and also provided insight into repurposing L-5-HTP for use in tumor immunotherapy. BMJ Publishing Group 2022-06-21 /pmc/articles/PMC9214382/ /pubmed/35728870 http://dx.doi.org/10.1136/jitc-2021-003957 Text en © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) . |
spellingShingle | Clinical/Translational Cancer Immunotherapy Huang, Jing Wang, Xiaobo Li, Bing Shen, Shiyu Wang, Ruina Tao, Hongru Hu, Junchi Yu, Jin Jiang, Hualiang Chen, Kaixian Luo, Cheng Dang, Yongjun Zhang, Yuanyuan L-5-hydroxytryptophan promotes antitumor immunity by inhibiting PD-L1 inducible expression |
title | L-5-hydroxytryptophan promotes antitumor immunity by inhibiting PD-L1 inducible expression |
title_full | L-5-hydroxytryptophan promotes antitumor immunity by inhibiting PD-L1 inducible expression |
title_fullStr | L-5-hydroxytryptophan promotes antitumor immunity by inhibiting PD-L1 inducible expression |
title_full_unstemmed | L-5-hydroxytryptophan promotes antitumor immunity by inhibiting PD-L1 inducible expression |
title_short | L-5-hydroxytryptophan promotes antitumor immunity by inhibiting PD-L1 inducible expression |
title_sort | l-5-hydroxytryptophan promotes antitumor immunity by inhibiting pd-l1 inducible expression |
topic | Clinical/Translational Cancer Immunotherapy |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9214382/ https://www.ncbi.nlm.nih.gov/pubmed/35728870 http://dx.doi.org/10.1136/jitc-2021-003957 |
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