Hydroxyproline metabolism enhances IFN-γ-induced PD-L1 expression and inhibits autophagic flux
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Hydroxyproline metabolism enhances IFN-γ-induced PD-L1 expression and inhibits autophagic flux. / Spangenberg, Stephan H; Palermo, Amelia; Gazaniga, Nathalia R; Martínez-Peña, Francisco; Guijas, Carlos; Chin, Emily N; Rinschen, Markus M; Sander, Philipp N; Webb, Bill; Pereira, Laura E; Jia, Ying; Meitz, Lance; Siuzdak, Gary; Lairson, Luke L.
in: CELL CHEM BIOL, Jahrgang 30, Nr. 9, 21.09.2023, S. 1115-1134.e10.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Hydroxyproline metabolism enhances IFN-γ-induced PD-L1 expression and inhibits autophagic flux
AU - Spangenberg, Stephan H
AU - Palermo, Amelia
AU - Gazaniga, Nathalia R
AU - Martínez-Peña, Francisco
AU - Guijas, Carlos
AU - Chin, Emily N
AU - Rinschen, Markus M
AU - Sander, Philipp N
AU - Webb, Bill
AU - Pereira, Laura E
AU - Jia, Ying
AU - Meitz, Lance
AU - Siuzdak, Gary
AU - Lairson, Luke L
N1 - Copyright © 2023 Elsevier Ltd. All rights reserved.
PY - 2023/9/21
Y1 - 2023/9/21
N2 - 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.
AB - 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.
KW - Autophagy
KW - B7-H1 Antigen/genetics
KW - Cell Line, Tumor
KW - Hydroxyproline
KW - Interferon-gamma/pharmacology
KW - Humans
U2 - 10.1016/j.chembiol.2023.06.016
DO - 10.1016/j.chembiol.2023.06.016
M3 - SCORING: Journal article
C2 - 37467751
VL - 30
SP - 1115-1134.e10
JO - CELL CHEM BIOL
JF - CELL CHEM BIOL
SN - 2451-9456
IS - 9
ER -
