STAT5-Activating Oncogenes Drive Oncostatin M Production Causing T Cell Exhaustion and Suppressive Myeloid Cell Recruitment

A connection between oncogenic signaling and immune evasion mechanisms was shown for different haematological malignancies such as the FLT3-ITD/ATF6/IRF7/IL-15 axis in acute myeloid leukemia (AML) or the JAK2/STAT3/PD-L1 axis in myeloproliferative neoplasms (MPN)(Mathew et al. Nat Med 2018; Prestipino et al. Sci Transl Med 2018). Recent data indicate that interfering with pathogenic cytokine signaling enhances response to immunotherapy in patients with non-small-cell lung cancer (NSCLC) and Hodgkin lymphoma (Mathew et al. Science 2024; Zak et al. Science 2024). We have previously demonstrated that oncogenic FLT3-ITD causes signal transducer and activator of transcription 5 (STAT5) activation thereby promoting MPN in mice (Müller et al. Leukemia 2016). Upon activation, STAT5 upregulates a set of target genes, among which is the IL-6 family cytokine Oncostatin M (OSM).

In the current study, we found that STAT5-activating oncogenes JAK2-V617F, BCR-ABL, and FLT3-ITD in hematopoietic cells induce the IL-6-family cytokine Oncostatin M (OSM) which acted immunosuppressive. Expression of the OSM receptor (OSMR) was limited to non-hematopoietic bone marrow (BM) stromal cells. OSM profoundly reprogrammed these cells, inducing the secretion of cytokines connected to T cell exhaustion, including IL-6 and MCP-1, and led to increased lactic acid production. OSM overexpression from hematopoietic cells in mice reduced T cells numbers and caused T cell exhaustion while showing elevated levels of pro-inflammatory cytokines including Csf1, Csf2, IL6, and chemokines such as Ccl2, Ccl3, Ccl4, and Ccl6. Furthermore, OSM induced expansion of myeloid-derived suppressor cells (MDSCs) thereby promoting immune escape of malignant hematopoietic cells. In murine in vivo models of AML or CML by transplantation of WT vs. Osm deficient BM retrovirally transduced with FLT3-ITD or BCR-ABL, respectively, into WT mice, mice receiving Osm^+/+ BM exhibited higher white blood cell counts, stronger expansion of EGFP⁺ and CD11b⁺Gr-1⁺ cells and shorter median survival compared to Osm^-/- animals. In mice with JAK2-V617F-driven polycythemia vera, Osm knockout reduced disease progression, including polyglobulia, splenomegaly, and osteofibrosis. JAK2-V617F Osm WT animals showed enrichment of phenotypic markers and genes indicative of T cell exhaustion compared to animals that had received Jak2-V617F⁺ Osm^+/+ BM. Furthermore, T cells from Jak2-V617F⁺ Osm^+/+ mice expressed higher levels of pro-inflammatory cytokines and chemokines including Csf1, Csf2, IL6, Ccl3, or Ccl4.

To correlate our findings from mice experiments in humans, we analyzed Osm expression in peripheral blood and BM isolated from patients with CML and found significantly higher levels compared to healthy controls. Additionally, we assessed OSM levels in AML and MPN patients’ plasma and observed substantially higher levels in patients with FLT3-ITD⁺ AML and active disease (i.e. first diagnosis, blast persistence, or relapse) as compared to FLT3-ITD⁺ patients in remission or FLT3-ITD^- patients. These findings support the concept that also in humans STAT5-inducing oncogenes enhance OSM transcription.

We then probed pharmacological inhibition of OSM by a monoclonal antibody or OSM receptor fusion protein (RFP)(Brolund et al. BMC Biotechnol 2011) in the JAK2-V617F mouse model. Both treatments reduced disease activity including polyglobulia and cytokine levels. OSM-RFP treatment additionally reduced osteosclerosis in JAK2-V617F animals.

In summary, our study indicates that STAT5-activating oncogenes drive OSM production thereby inducing MDSC recruitment and T cell exhaustion. Investigating the potential cooperation between OSM/OSMR inhibition and immunotherapy-based approaches may hold promise for improving outcomes in affected patients.