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Sci Transl Med. 2018 Feb 21;10(429). pii: eaam7729. doi: 10.1126/scitranslmed.aam7729.

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

Author information

1
Department of Hematology and Oncology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg 79106, Germany.
2
Faculty of Biology, Albert Ludwigs University of Freiburg, Freiburg 79104, Germany.
3
Institute of Surgical Pathology, Faculty of Medicine, University of Freiburg, Freiburg 79106, Germany.
4
Max Planck Institute for Immunobiology and Epigenetics, Freiburg 79108, Germany.
5
Department of Immunology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia.
6
School of Medicine, University of Queensland, Herston, Queensland 4006, Australia.
7
Institute of Molecular Medicine and Cell Research, Faculty of Medicine, University of Freiburg, Freiburg 79085, Germany.
8
German Cancer Consortium (DKTK) partner site Freiburg, Freiburg, Germany.
9
German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
10
Institute of Experimental Dermatology, Institute of Cardiogenetics, University of Lübeck, Lübeck 23562, Germany.
11
Berta-Ottenstein Programme, Faculty of Medicine, University of Freiburg, Freiburg 79106, Germany.
12
Department of Radiation Oncology, Faculty of Medicine, University of Freiburg, Freiburg 79106, Germany.
13
Department of Nuclear Medicine, Faculty of Medicine, University of Freiburg, Freiburg 79106, Germany.
14
Spemann Graduate School of Biology and Medicine, University of Freiburg, Freiburg 79085, Germany.
15
Center for Chronic Immunodeficiency, Medical Center, University of Freiburg, Freiburg 79106, Germany.
16
BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg 79104, Germany.
17
Internal Medicine II, Department of Hematology and Oncology, University Hospital of Jena, Jena 07745, Germany.
18
Leibniz Institute on Aging-Fritz Lipmann Institute, Jena 07745, Germany.
19
Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.
20
Unit of Experimental Hematology, San Raffaele Scientific Institute, and University of Vita-Salute San Raffaele, Milano 20132, Italy.
21
Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.
22
University of Queensland, Herston, Queensland 4072, Australia.
23
Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA.
24
Department of Hematology and Oncology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg 79106, Germany. robert.zeiser@uniklinik-freiburg.de.

Abstract

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.

PMID:
29467301
PMCID:
PMC6034655
DOI:
10.1126/scitranslmed.aam7729
[Indexed for MEDLINE]
Free PMC Article

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