Cellular expression of PD-1, PD-L1 and CTLA-4 in patients with JAK2V617F mutated myeloproliferative disorders.

Abstract

Objectives: The acquired, somatic JAK2^V617F mutation is the most common molecular aberration in patients with myeloproliferative neoplasms (MPN) and also significantly involved in the regulation of T cell immunity. PD-1, PD-L1 and CTLA-4 are key immune checkpoint regulators that are elevated in patients with solid tumors, infectious diseases and chronic inflammation. We aimed further investigating the significance of immune checkpoint expression in JAK2^V617F positive MPN.

Methods: The surface expression of PD-L1, PD-1 and CTLA-4 on peripheral blood leukocytes was determined by flow cytometry in 27 patients with JAK2^V617F positive MPN and in a control group of 26 healthy individuals and analyzed by immune checkpoint and leukocyte subpopulation. In addition, the concentration of soluble PD-L1 (sPD-L1) in plasma was examined by ELISA.

Results: PD-1, PD-L1 and CTLA-4 are significantly overexpressed on the surface of granulocytes in JAK2 positive patients compared to the control group. Soluble PD-L1 (sPD-L1) is elevated in the plasma of JAK2 positive patients and increases with decreased renal function. In CD8+ T-cells and CD4+ T-cells there is a significant negative correlation between PD-1 expression or sPD-L1 concentration and their corresponding cell count.

Conclusions: Our study shows a significant increase of immune checkpoint regulators on the cellular surface as well as soluble PD-L1 in JAK2 mutated patients compared to healthy individuals. Increased activation of the JAK2/STAT signaling pathway by JAK2^V617F appears to be a mechanism of reduced immune activation in patients with MPN. Immune checkpoint inhibition might therefore represent a potential additional therapeutic target in this disease group.