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.