STAT5-activating oncogenes drive Oncostatin M production causing T cell exhaustion and suppressive myeloid cell recruitment

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. To investigate the effects of OSM deficiency in transplanted hematopoietic cells (Osm+/+ vs. Osm-/-) harboring the JAK2V617F mutation on T cells, splenic Thy1.2+ cells were isolated, RNA was extracted and further processed for RNA-sequencing.