Hydroxyproline metabolism enhances IFN-γ-induced PD-L1 expression and inhibits autophagic flux
Copyright © 2023 Elsevier Ltd. All rights reserved..
The immune checkpoint protein PD-L1 plays critical roles in both immune system homeostasis and tumor progression. Impaired PD-1/PD-L1 function promotes autoimmunity and PD-L1 expression within tumors promotes immune evasion. If and how changes in metabolism or defined metabolites regulate PD-L1 expression is not fully understood. Here, using a metabolomics activity screening-based approach, we have determined that hydroxyproline (Hyp) significantly and directly enhances adaptive (i.e., IFN-γ-induced) PD-L1 expression in multiple relevant myeloid and cancer cell types. Mechanistic studies reveal that Hyp acts as an inhibitor of autophagic flux, which allows it to regulate this negative feedback mechanism, thereby contributing to its overall effect on PD-L1 expression. Due to its prevalence in fibrotic tumors, these findings suggest that hydroxyproline could contribute to the establishment of an immunosuppressive tumor microenvironment and that Hyp metabolism could be targeted to pharmacologically control PD-L1 expression for the treatment of cancer or autoimmune diseases.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:30 |
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| Enthalten in: |
Cell chemical biology - 30(2023), 9 vom: 21. Sept., Seite 1115-1134.e10 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Spangenberg, Stephan H [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 26.09.2023 Date Revised 26.09.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.chembiol.2023.06.016 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM359682073 |
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| 520 | |a The immune checkpoint protein PD-L1 plays critical roles in both immune system homeostasis and tumor progression. Impaired PD-1/PD-L1 function promotes autoimmunity and PD-L1 expression within tumors promotes immune evasion. If and how changes in metabolism or defined metabolites regulate PD-L1 expression is not fully understood. Here, using a metabolomics activity screening-based approach, we have determined that hydroxyproline (Hyp) significantly and directly enhances adaptive (i.e., IFN-γ-induced) PD-L1 expression in multiple relevant myeloid and cancer cell types. Mechanistic studies reveal that Hyp acts as an inhibitor of autophagic flux, which allows it to regulate this negative feedback mechanism, thereby contributing to its overall effect on PD-L1 expression. Due to its prevalence in fibrotic tumors, these findings suggest that hydroxyproline could contribute to the establishment of an immunosuppressive tumor microenvironment and that Hyp metabolism could be targeted to pharmacologically control PD-L1 expression for the treatment of cancer or autoimmune diseases | ||
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| 700 | 1 | |a Gazaniga, Nathalia R |e verfasserin |4 aut | |
| 700 | 1 | |a Martínez-Peña, Francisco |e verfasserin |4 aut | |
| 700 | 1 | |a Guijas, Carlos |e verfasserin |4 aut | |
| 700 | 1 | |a Chin, Emily N |e verfasserin |4 aut | |
| 700 | 1 | |a Rinschen, Markus M |e verfasserin |4 aut | |
| 700 | 1 | |a Sander, Philipp N |e verfasserin |4 aut | |
| 700 | 1 | |a Webb, Bill |e verfasserin |4 aut | |
| 700 | 1 | |a Pereira, Laura E |e verfasserin |4 aut | |
| 700 | 1 | |a Jia, Ying |e verfasserin |4 aut | |
| 700 | 1 | |a Meitz, Lance |e verfasserin |4 aut | |
| 700 | 1 | |a Siuzdak, Gary |e verfasserin |4 aut | |
| 700 | 1 | |a Lairson, Luke L |e verfasserin |4 aut | |
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