Winkler Christoph, Anliker Markus, Schmidt Stefan, Feistritzer Clemens, Höchsmann Britta, Schrezenmeier Hubert, Siller Anita, Griesmacher Andrea, Loacker Lorin
Central Institute of Clinical and Chemical Laboratory Diagnostics, University Hospital of Innsbruck, Innsbruck, Austria.
Department of Internal Medicine V, Hematology and Oncology, Medical University of Innsbruck, Innsbruck, Austria.
Clin Chem Lab Med. 2025 Jul 3. doi: 10.1515/cclm-2025-0306.
The acquired, somatic JAK2 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 positive MPN.
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 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.
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.
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 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.
获得性体细胞JAK2突变是骨髓增殖性肿瘤（MPN）患者中最常见的分子异常，并且在T细胞免疫调节中也发挥重要作用。PD-1、PD-L1和CTLA-4是关键的免疫检查点调节因子，在实体瘤、传染病和慢性炎症患者中表达升高。我们旨在进一步研究免疫检查点表达在JAK2阳性MPN中的意义。
通过流式细胞术测定27例JAK2阳性MPN患者外周血白细胞上PD-L1、PD-1和CTLA-4的表面表达，并在26名健康个体组成的对照组中进行检测，同时按免疫检查点和白细胞亚群进行分析。此外，采用酶联免疫吸附测定法检测血浆中可溶性PD-L1（sPD-L1）的浓度。
与对照组相比，JAK2阳性患者的粒细胞表面PD-1、PD-L1和CTLA-4显著过表达。JAK2阳性患者血浆中可溶性PD-L1（sPD-L1）升高，且随肾功能下降而增加。在CD8+T细胞和CD4+T细胞中，PD-1表达或sPD-L1浓度与相应细胞计数之间存在显著负相关。
我们的研究表明，与健康个体相比，JAK2突变患者细胞表面的免疫检查点调节因子以及可溶性PD-L1显著增加。JAK2对JAK2/STAT信号通路的激活增加似乎是MPN患者免疫激活降低的一种机制。因此，免疫检查点抑制可能是该疾病组潜在的额外治疗靶点。
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