The Role of the IL-6 Cytokine Family in Epithelial-Mesenchymal Plasticity in Cancer Progression.

Epithelial-mesenchymal plasticity (EMP) plays critical roles during embryonic development, wound repair, fibrosis, inflammation and cancer. During cancer progression, EMP results in heterogeneous and dynamic populations of cells with mixed epithelial and mesenchymal characteristics, which are required for local invasion and metastatic dissemination. Cancer development is associated with an inflammatory microenvironment characterized by the accumulation of multiple immune cells and pro-inflammatory mediators, such as cytokines and chemokines. Cytokines from the interleukin 6 (IL-6) family play fundamental roles in mediating tumour-promoting inflammation within the tumour microenvironment, and have been associated with chronic inflammation, autoimmunity, infectious diseases and cancer, where some members often act as diagnostic or prognostic biomarkers. All IL-6 family members signal through the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway and are able to activate a wide array of signalling pathways and transcription factors. In general, IL-6 cytokines activate EMP processes, fostering the acquisition of mesenchymal features in cancer cells. However, this effect may be highly context dependent. This review will summarise all the relevant literature related to all members of the IL-6 family and EMP, although it is mainly focused on IL-6 and oncostatin M (OSM), the family members that have been more extensively studied.

New perspectives in cancer immunotherapy: targeting IL-6 cytokine family.

Chronic inflammation has been recognized as a canonical cancer hallmark. It is orchestrated by cytokines, which are master regulators of the tumor microenvironment (TME) as they represent the main communication bridge between cancer cells, the tumor stroma, and the immune system. Interleukin (IL)-6 represents a keystone cytokine in the link between inflammation and cancer. Many cytokines from the IL-6 family, which includes IL-6, oncostatin M, leukemia inhibitory factor, IL-11, IL-27, IL-31, ciliary neurotrophic factor, cardiotrophin 1, and cardiotrophin-like cytokine factor 1, have been shown to elicit tumor-promoting roles by modulating the TME, making them attractive therapeutic targets for cancer treatment.The development of immune checkpoint blockade (ICB) immunotherapies has radically changed the outcome of some cancers including melanoma, lung, and renal, although not without hurdles. However, ICB shows limited efficacy in other solid tumors. Recent reports support that chronic inflammation and IL-6 cytokine signaling are involved in resistance to immunotherapy. This review summarizes the available preclinical and clinical data regarding the implication of IL-6-related cytokines in regulating the immune TME and the response to ICB. Moreover, the potential clinical benefit of combining ICB with therapies targeting IL-6 cytokine members for cancer treatment is discussed.

Stromal oncostatin M cytokine promotes breast cancer progression by reprogramming the tumor microenvironment.

The tumor microenvironment (TME) is reprogrammed by cancer cells and participates in all stages of tumor progression. The contribution of stromal cells to the reprogramming of the TME is not well understood. Here, we provide 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. OSM receptor (OSMR) deletion in a multistage breast cancer model halted tumor progression. We ascribed causality to the stromal function of the OSM axis by demonstrating reduced tumor burden of syngeneic tumors implanted in mice lacking OSMR. Single-cell and bioinformatic analysis of murine and human breast tumors 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 and elicited the secretion of VEGF and proinflammatory chemokines CXCL1 and CXCL16, leading to increased myeloid cell recruitment. Collectively, our data support the notion that the stromal OSM/OSMR axis reprograms the immune and nonimmune microenvironment and plays a key role in breast cancer progression.