Oncogenic JAK2causes PD-L1 expression, mediating immune escape in myeloproliferative neoplasms
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Oncogenic JAK2causes PD-L1 expression, mediating immune escape in myeloproliferative neoplasms. / Prestipino, Alessandro; Emhardt, Alica J; Aumann, Konrad; O'Sullivan, David; Gorantla, Sivahari P; Duquesne, Sandra; Melchinger, Wolfgang; Braun, Lukas; Vuckovic, Slavica; Boerries, Melanie; Busch, Hauke; Halbach, Sebastian; Pennisi, Sandra; Poggio, Teresa; Apostolova, Petya; Veratti, Pia; Hettich, Michael; Niedermann, Gabriele; Bartholomä, Mark; Shoumariyeh, Khalid; Jutzi, Jonas S; Wehrle, Julius; Dierks, Christine; Becker, Heiko; Schmitt-Graeff, Annette; Follo, Marie; Pfeifer, Dietmar; Rohr, Jan; Fuchs, Sebastian; Ehl, Stephan; Hartl, Frederike A; Minguet, Susana; Miething, Cornelius; Heidel, Florian H; Kröger, Nicolaus; Triviai, Ioanna; Brummer, Tilman; Finke, Jürgen; Illert, Anna L; Ruggiero, Eliana; Bonini, Chiara; Duyster, Justus; Pahl, Heike L; Lane, Steven W; Hill, Geoffrey R; Blazar, Bruce R; von Bubnoff, Nikolas; Pearce, Erika L; Zeiser, Robert.
In: SCI TRANSL MED, Vol. 10, 21.02.2018, p. 429.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Oncogenic JAK2causes PD-L1 expression, mediating immune escape in myeloproliferative neoplasms
AU - Prestipino, Alessandro
AU - Emhardt, Alica J
AU - Aumann, Konrad
AU - O'Sullivan, David
AU - Gorantla, Sivahari P
AU - Duquesne, Sandra
AU - Melchinger, Wolfgang
AU - Braun, Lukas
AU - Vuckovic, Slavica
AU - Boerries, Melanie
AU - Busch, Hauke
AU - Halbach, Sebastian
AU - Pennisi, Sandra
AU - Poggio, Teresa
AU - Apostolova, Petya
AU - Veratti, Pia
AU - Hettich, Michael
AU - Niedermann, Gabriele
AU - Bartholomä, Mark
AU - Shoumariyeh, Khalid
AU - Jutzi, Jonas S
AU - Wehrle, Julius
AU - Dierks, Christine
AU - Becker, Heiko
AU - Schmitt-Graeff, Annette
AU - Follo, Marie
AU - Pfeifer, Dietmar
AU - Rohr, Jan
AU - Fuchs, Sebastian
AU - Ehl, Stephan
AU - Hartl, Frederike A
AU - Minguet, Susana
AU - Miething, Cornelius
AU - Heidel, Florian H
AU - Kröger, Nicolaus
AU - Triviai, Ioanna
AU - Brummer, Tilman
AU - Finke, Jürgen
AU - Illert, Anna L
AU - Ruggiero, Eliana
AU - Bonini, Chiara
AU - Duyster, Justus
AU - Pahl, Heike L
AU - Lane, Steven W
AU - Hill, Geoffrey R
AU - Blazar, Bruce R
AU - von Bubnoff, Nikolas
AU - Pearce, Erika L
AU - Zeiser, Robert
N1 - Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
PY - 2018/2/21
Y1 - 2018/2/21
N2 - Recent evidence has revealed that oncogenic mutations may confer immune escape. A better understanding of how an oncogenic mutation affects immunosuppressive programmed death ligand 1 (PD-L1) expression may help in developing new therapeutic strategies. We show that oncogenic JAK2 (Janus kinase 2) activity caused STAT3 (signal transducer and activator of transcription 3) and STAT5 phosphorylation, which enhanced PD-L1 promoter activity and PD-L1 protein expression in JAK2V617F-mutant cells, whereas blockade of JAK2 reduced PD-L1 expression in myeloid JAK2V617F-mutant cells. PD-L1 expression was higher on primary cells isolated from patients with JAK2V617F-myeloproliferative neoplasms (MPNs) compared to healthy individuals and declined upon JAK2 inhibition. JAK2V617Fmutational burden, pSTAT3, and PD-L1 expression were highest in primary MPN patient-derived monocytes, megakaryocytes, and platelets. PD-1 (programmed death receptor 1) inhibition prolonged survival in human MPN xenograft and primary murine MPN models. This effect was dependent on T cells. Mechanistically, PD-L1 surface expression in JAK2V617F-mutant cells affected metabolism and cell cycle progression of T cells. In summary, we report that in MPN, constitutive JAK2/STAT3/STAT5 activation, mainly in monocytes, megakaryocytes, and platelets, caused PD-L1-mediated immune escape by reducing T cell activation, metabolic activity, and cell cycle progression. The susceptibility of JAK2V617F-mutant MPN to PD-1 targeting paves the way for immunomodulatory approaches relying on PD-1 inhibition.
AB - Recent evidence has revealed that oncogenic mutations may confer immune escape. A better understanding of how an oncogenic mutation affects immunosuppressive programmed death ligand 1 (PD-L1) expression may help in developing new therapeutic strategies. We show that oncogenic JAK2 (Janus kinase 2) activity caused STAT3 (signal transducer and activator of transcription 3) and STAT5 phosphorylation, which enhanced PD-L1 promoter activity and PD-L1 protein expression in JAK2V617F-mutant cells, whereas blockade of JAK2 reduced PD-L1 expression in myeloid JAK2V617F-mutant cells. PD-L1 expression was higher on primary cells isolated from patients with JAK2V617F-myeloproliferative neoplasms (MPNs) compared to healthy individuals and declined upon JAK2 inhibition. JAK2V617Fmutational burden, pSTAT3, and PD-L1 expression were highest in primary MPN patient-derived monocytes, megakaryocytes, and platelets. PD-1 (programmed death receptor 1) inhibition prolonged survival in human MPN xenograft and primary murine MPN models. This effect was dependent on T cells. Mechanistically, PD-L1 surface expression in JAK2V617F-mutant cells affected metabolism and cell cycle progression of T cells. In summary, we report that in MPN, constitutive JAK2/STAT3/STAT5 activation, mainly in monocytes, megakaryocytes, and platelets, caused PD-L1-mediated immune escape by reducing T cell activation, metabolic activity, and cell cycle progression. The susceptibility of JAK2V617F-mutant MPN to PD-1 targeting paves the way for immunomodulatory approaches relying on PD-1 inhibition.
KW - Journal Article
U2 - 10.1126/scitranslmed.aam7729
DO - 10.1126/scitranslmed.aam7729
M3 - SCORING: Journal article
C2 - 29467301
VL - 10
SP - 429
JO - SCI TRANSL MED
JF - SCI TRANSL MED
SN - 1946-6234
ER -