STAT5-activating oncogenes drive Oncostatin M production causing T cell exhaustion and suppressive myeloid cell recruitment [Thy1.2+ splenocytes]

Understanding the interplay between oncogenic mutations and immune evasion of cancer cells could help to improve cancer immunotherapy in hematological malignancies. We found that the STAT5-activating oncogenes BCR-ABL, JAK2-V617F, and FLT3-ITD induce Oncostatin M (OSM) which acted immunosuppressive. OSM profoundly reprogrammed bone marrow (BM) stromal cells, inducing the secretion of cytokines connected to T cell exhaustion, including IL-6 and MCP-1. OSM overexpressing mice exhibited reduced T cells numbers, more T cell exhaustion and increased lactic acid production by stroma cells. OSM induced expansion of myeloid-derived suppressor cells (MDSCs) thereby promoting immune escape of malignant hematopoietic cells. Osm knockout reduced disease progression and T cell exhaustion in mice with JAK2-V617F-driven polycythemia vera. Consistently, pharmacological inhibition of OSM reduced disease activity and cytokine production. Our study indicates that STAT5-activating oncogenes drive OSM production thereby inducing MDSC recruitment and T cell exhaustion. Overall design: To investigate the effects of OSM overexpression by transplanted hematopoietic cells on T cells in an in vivo murine model, splenic Thy1.2+ cells were isolated, RNA was extracted and further processed for RNA-sequencing. T cells from animals transplanted with an empty MiG-vector were utilized as controls.

阐明致癌突变与癌细胞免疫逃逸之间的相互作用，可为改善血液系统恶性肿瘤的癌症免疫治疗提供理论依据。本研究发现，激活STAT5的致癌基因BCR-ABL、JAK2-V617F与FLT3-ITD可诱导抑癌素M（Oncostatin M）的表达，该因子具有免疫抑制功能。OSM可显著重编程骨髓（bone marrow, BM）基质细胞，诱导其分泌与T细胞耗竭相关的细胞因子，包括IL-6与MCP-1。过表达OSM的小鼠体内T细胞数量减少、T细胞耗竭程度加剧，且基质细胞的乳酸生成量升高。OSM可诱导髓系来源抑制细胞（myeloid-derived suppressor cells, MDSCs）的扩增，进而促进恶性造血细胞的免疫逃逸。在JAK2-V617F驱动的真性红细胞增多症小鼠模型中，敲除Osm基因可延缓疾病进展并减轻T细胞耗竭。与之相符的是，通过药理学手段抑制OSM可降低疾病活动度并减少细胞因子分泌。本研究表明，激活STAT5的致癌基因通过驱动OSM的产生，进而诱导MDSCs募集与T细胞耗竭。实验整体设计：为探究移植的造血细胞过表达OSM对体内小鼠模型中T细胞的影响，本研究分离了脾脏Thy1.2阳性细胞，提取RNA并进行RNA测序（RNA-sequencing）。以移植空MiG载体的动物的T细胞作为对照。