Chronic inflammation in the tumour microenvironment (TME) is nowadays accepted as a canonical hallmark of cancer and a major driver for metastasis, leading cause of death in breast cancer patients. The major regulators of inflammation are cytokines, which are small-secreted molecules involved in cell-to-cell communication. Most cell types - including innate and adaptive immune cells as well as stromal and cancer cells - can secrete cytokines and respond to them. We recently discovered that the cytokine Oncostatin M (OSM) plays an important role in breast cancer progression by activating cancer-associated fibroblasts and promoting myeloid recruitment1. However, the fundamental question at this point is if OSM promotes immune suppression in breast cancer and how it does it.

This current unpublished work examines the effect of OSM on tumour immune remodelling and immune suppression by combining molecular biology techniques, flow cytometry analyses, and multiomics (including single cell RNA sequencing and proteomics) on patients’ data, immunocompetent murine models and cell lines.

Our findings identified myeloid cells as the primary source of OSM in human breast cancer and healthy breast. In vivo studies showed that activation of the OSM receptor OSMR shapes the cytokine profiling of the TME, favouring the secretion of other proinflammatory cytokines and chemokines (such as Il1b, Cxcl1, Cxcl2, Ccl2 and Csfs) that contribute to an immunosuppressed environment. In addition, OSM promotes gene signatures of MDSCs, increases the expression of immune checkpoint regulators (PD-L1 and PD-L2), and phagocytosis-inhibiting signals (CD47-SIRPA axis), indicating a relevant role for OSM signalling in immune regulation. Furthermore, we characterized that OSM stimulation promotes metabolic reprogramming of cancer cells, integrin signalling and ECM remodelling. Our findings revealed a common mechanism via hypoxia inducible factors for both OSM-induced metabolic reprogramming and immune evasion. Finally, therapeutic inhibition of OSM signalling with an anti-OSM blocking antibody synergises with anti-PDL1 in immune checkpoint blockade resistant models.

Our work sheds light on the effects of OSM signalling in the immune response and lays the groundwork for further development of targeted interventions to disrupt this pro-tumoral signalling.

1. Araujo AM, Abaurrea A, Azcoaga P, et al. Stromal oncostatin M cytokine promotes breast cancer progression by reprogramming the tumor microenvironment. J Clin Invest. 2022;132(7):e148667. doi:10.1172/JCI148667 This work is funded by the Spanish Ministry of Science and Innovation (CNS2023-145020 and PID2024-158438OB-I00); AECC (LABAE247490MUNO); FERO foundation and Ikerbasque Basque Research Foundation.