Research ArticleCancer

Oncogenic JAK2V617F causes PD-L1 expression, mediating immune escape in myeloproliferative neoplasms

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Science Translational Medicine  21 Feb 2018:
Vol. 10, Issue 429, eaam7729
DOI: 10.1126/scitranslmed.aam7729

Cancers JAK up an immune checkpoint

Myeloproliferative neoplasms, a group of hematologic cancers, are associated with mutations activating the JAK2 oncogene. JAK2 is located on chromosome 9, in the vicinity of the immunosuppressive PD-L1 gene, and Prestipino et al. discovered that myeloproliferative cancers with overactive JAK2 generally have increased PD-L1 as well. Although PD-L1 helps cancers evade the immune system, immune checkpoint inhibitors developed in recent years provide a way to block its function and turn PD-L1 expression into a therapeutic vulnerability for the tumors, as the authors demonstrate in this study.


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. JAK2V617F mutational 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.

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