Oncogenic JAK2 ^V617F causes PD-L1 expression, mediating immune escape in myeloproliferative neoplasms

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 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.

B‐cell frequencies and immunoregulatory phenotypes in myeloproliferative neoplasms: Influence of ruxolitinib, interferon‐α2, or combination treatment

“…This is in keeping with a previous finding of increased gene expression of PD‐L1 in peripheral whole blood of patients with MPNs compared with HDs . Contrarily, a recent study has shown that the JAK2 ‐V617F mutation increases the expression of PD‐L1 on various cell types in patients with MPNs, but not in B cells . Upregulated expression of PD‐L1 on Bregs has also been observed in patients with invasive breast cancer, where the interaction of B‐cell PD‐L1 with PD‐1 on T cells promoted a Treg phenotype, and tumor‐infiltrating B cells have been suggested to play an important role in promoting tumor progression .…”

IL-6/JAK1 pathway drives PD-L1 Y112 phosphorylation to promote cancer immune evasion

“…Activated JAK1 and JAK2 are known to upregulate the expression of immune checkpoint molecules (48,49). However, the loss of function of JAK family members also contributes to the resistance of cancer to anti-CTLA-4 and anti-PD-1 therapy by reducing neoantigen presentation and IFN-γ-induced cancer cell apoptosis in patients (33,34,50,51).…”

Risk stratification for lung adenocarcinoma on EGFR and TP53 mutation status, chemotherapy, and PD‐L1 immunotherapy

“…PD‐L1 was expressed in RET (rearranged during transfection)‐rearranged NSCLC, and kinase fusions, such as the fusion of PICALM and RET , are associated with tumorigenesis . Inhibition of BRD2, which has a similar effect on STAT5, is an appealing therapeutic strategy for hematologic malignancies, consistent with the finding that enhanced STAT5 phosphorylation can increase PD‐L1 expression to produce PD‐L1–mediated immune escape . Inhibition of both BET bromodomain (eg, BRD2) and immune checkpoints (eg, PD‐1) is also a promising approach to treat solid tumors such as LUAD …”