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 JAK2-mutant cells, whereas blockade of JAK2 reduced PD-L1 expression in myeloid JAK2-mutant cells. PD-L1 expression was higher on primary cells isolated from patients with JAK2-myeloproliferative neoplasms (MPNs) compared to healthy individuals and declined upon JAK2 inhibition. JAK2 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 JAK2-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-mutant MPN to PD-1 targeting paves the way for immunomodulatory approaches relying on PD-1 inhibition.

Key Points• GVHD induction is dependent on functional miR-155 in DCs of the allo-HCT recipient.• MiR-155 deficiency reduces ATP-mediated cell migration, ERK and inflammasome activation, and IL-1b production of DCs.The successful treatment of acute leukemias with allogeneic hematopoietic cell transplantation (allo-HCT) is limited by acute graft-versus-host disease (GVHD). Because microRNA-155 (miR-155) regulates activation of the innate immune system, we aimed to determine its function in dendritic cells (DCs) during GVHD in an experimental model. We observed that miR-155 deficiency of the recipient led to improved survival, reduced serum levels of proinflammatory cytokines, and lower GVHD histopathology scores. In addition, miR-155 2/2 bone marrow chimeric mice receiving allo-HCT and miR-155 2/2 DCs showed that miR-155 deficiency in the DC compartment was responsible for protection from GVHD. Activated miR-155 2/2 DCs displayed lower expression of various purinergic receptors and impaired migration toward adenosine triphosphate (ATP). Microarray analysis of lipopolysaccharide/ATP-stimulated miR-155 2/2 DCs revealed mitogen-activated protein kinase pathway dysregulation and reduced inflammasome-associated gene expression. Consistent with this gene expression data, we observed reduced ERK activation, caspase-1 cleavage, and IL-1b production in miR-155 2/2 DCs. The connection between miR-155 and inflammasome activation was supported by the fact that Nlrp3/miR-155 double-knockout allo-HCT recipient mice had no increased protection from GVHD compared with Nlrp3 2/2 recipients. This study indicates that during GVHD, miR-155 promotes DC migration toward sites of ATP release accompanied by inflammasome activation. Inhibiting proinflammatory miR-155 by antagomir treatment could help reduce this complication of allo-HCT. (Blood. 2015;126(1):103-112)

Key Points Cav-1–deficient T cells preferentially differentiate into Tregs, which translates into lower GVHD severity in mice. Reduced TCR:Lck clustering in Cav-1–deficient T cells is responsible for reduced TCR downstream signaling events promoting Treg differentiation.