The tumour microenvironment (TME) is reprogrammed by cancer cells and participates in all stages of tumour progression. The contribution of stromal cells to the reprogramming of the TME is not well-understood. Here we provide solid evidence of the role of the cytokine Oncostatin M (OSM) as central node for multicellular interactions between immune and nonimmune stromal cells and the epithelial cancer cell compartment. Oncostatin M Receptor (OSMR) deletion in a multistage breast cancer model halted tumour progression. We ascribed causality to the stromal function of OSM axis by demonstrating reduced tumour burden of syngeneic tumours implanted in mice lacking OSMR. Single-cell and bioinformatic analysis of murine and human breast tumours revealed that OSM expression was restricted to myeloid cells, whereas OSMR was detected predominantly in fibroblasts and, to a lower extent, cancer cells. Myeloid-derived OSM reprogrammed fibroblasts to a more contractile and tumorigenic phenotype, elicited the secretion of VEGF and pro-inflammatory chemokines CXCL1 and CXCL16, leading to increased neutrophil and macrophage recruitment. Collectively, our data support that stromal OSM:OSMR axis reprograms the immune and non-immune microenvironment and plays a key role in breast cancer progression.

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Inflammasomes are cytosolic signaling hubs that promote the inflammatory response (i.e. an immune reaction to counteract threats in physiological conditions). Their potential role in lymphomagenesis remains to be elucidated. Depending on the context, innate immune cells, such as macrophages, may induce inflammation that contributes to the anti-tumor function; however, if uncontrolled, inflammation can promote cancer development. Here, we exploited bioinformatic tools, TCGA data, and tumor tissue samples from patients with diffuse large B-cell lymphoma (DLBCL), one of the most frequent non-Hodgkin lymphomas of B-cell origin, to investigate the distribution of the different immune cell subpopulations in DLBCL samples in order to characterize the immune landscape of their microenvironment. We found a clear prominence of macrophages in the DLBCL microenvironment. Particularly, the proportions of resting M0 and pro-inflammatory M1 macrophages were higher in DLBCL than spleen samples (controls). As each inflammasome has unique sensor activation and platform assembly mechanisms, we examined the expression of a large panel of inflammasome actors. We found that inflammasome components, cytokines and Toll-like receptors were upregulated in DLBCL samples, particularly in M0 and M1 macrophages, compared with controls. Moreover, their expression level was positively correlated with that of CD68 (a pan-macrophage marker). We confirmed the positive correlation between CD68 and IRF8 expression at the protein level in DLBCL tissue samples, where we observed increased infiltration of CD68- and IRF8-positive cells compared with normal lymph nodes. Altogether, our results highlight the inflammatory status of the DLBCL microenvironment orchestrated by macrophages. More work is needed to understand the complexity and potential therapeutic implications of inflammasomes in DLBCL.

Cytokines are key players in inflammation, a process associated with tumour initiation, angiogenesis and metastasis. However, the interplay between inflammation and other cell types in the tumour microenvironment is not well understood. Here we show that the IL6-related proinflammatory cytokine Oncostatin M (OSM) is a central node for multicellular interactions. Myeloid-derived OSM reprogrammes cancer-associated fibroblasts (CAFs) and cancer cells, promoting breast cancer progression. In addition, OSM induces, in both cell types, the secretion of inflammatory cytokines and chemokines, which in turn reinforce myeloid tumour infiltration. OSM is increased in cancer stroma and is associated with poor prognosis in multiple cancer types. Oncostatin M receptor (OSMR) deletion in stroma and in a multistage breast cancer mouse model delays tumour onset, tumour growth and reduces metastatic burden. Our results reveal an unprecedented tumour-promoting paracrine OSM:OSMR signalling crosstalk encompassing myeloid cells, CAFs and tumour cells, thus encouraging therapeutic strategies aimed at targeting this oncogenic axis in breast cancer.