| Autor: |
Alessandro, Prestipino, Alica J, Emhardt, Konrad, Aumann, David, O'Sullivan, Sivahari P, Gorantla, Sandra, Duquesne, Wolfgang, Melchinger, Lukas, Braun, Slavica, Vuckovic, Melanie, Boerries, Hauke, Busch, Sebastian, Halbach, Sandra, Pennisi, Teresa, Poggio, Petya, Apostolova, Pia, Veratti, Michael, Hettich, Gabriele, Niedermann, Mark, Bartholomä, Khalid, Shoumariyeh, Jonas S, Jutzi, Julius, Wehrle, Christine, Dierks, Heiko, Becker, Annette, Schmitt-Graeff, Marie, Follo, Dietmar, Pfeifer, Jan, Rohr, Sebastian, Fuchs, Stephan, Ehl, Frederike A, Hartl, Susana, Minguet, Cornelius, Miething, Florian H, Heidel, Nicolaus, Kröger, Ioanna, Triviai, Tilman, Brummer, Jürgen, Finke, Anna L, Illert, Eliana, Ruggiero, Chiara, Bonini, Justus, Duyster, Heike L, Pahl, Steven W, Lane, Geoffrey R, Hill, Bruce R, Blazar, Nikolas, von Bubnoff, Erika L, Pearce, Robert, Zeiser |
| Rok vydání: |
2017 |
| Předmět: |
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| Zdroj: |
Science translational medicine. 10(429) |
| ISSN: |
1946-6242 |
| Popis: |
Recent evidence has revealed that oncogenic mutations may confer immune escape. A better understanding of how an oncogenic mutation affects immunosuppressive PD-L1 expression may help in developing new therapeutic strategies. Here, we show that oncogenic JAK2 activity caused STAT3 and STAT5 phosphorylation, which enhanced PD-L1 promoter activity and PD-L1 protein expression in JAK2(V617F)-mutant cells, whereas blockade of JAK2 reduced PD-L1 expression in myeloid JAK2(V617F)-mutant cells. PD-L1 expression was higher on primary cells isolated from patients with JAK2(V617F)-myeloproliferative neoplasms (MPN) compared to healthy individuals and declined upon JAK2 inhibition. JAK2(V617F) mutational burden, pSTAT3, and PD-L1 expression were highest in primary MPN patient-derived monocytes, megakaryocytes, and platelets. PD-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 JAK2(V617F)-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 JAK2(V617F)-mutant MPN to PD-1 targeting paves the way for immunomodulatory approaches relying on PD-1 inhibition. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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