Tumor‐associated macrophage‐derived inflammatory cytokine enhances malignant potential of malignant pleural mesothelioma

Malignant pleural mesothelioma (MPM) is an asbestos‐related aggressive malignant neoplasm. Due to the difficulty of achieving curative surgical resection in most patients with MPM, a combination chemotherapy of cisplatin and pemetrexed has been the only approved regimen proven to improve the prognosis of MPM. However, the median overall survival time is at most 12 mo even with this regimen. There has been therefore a pressing need to develop a novel chemotherapeutic strategy to bring about a better outcome for MPM. We found that expression of interleukin‐1 receptor (IL‐1R) was upregulated in MPM cells compared with normal mesothelial cells. We also investigated the biological significance of the interaction between pro‐inflammatory cytokine IL‐1β and the IL‐1R in MPM cells. Stimulation by IL‐1β promoted MPM cells to form spheroids along with upregulating a cancer stem cell marker CD26. We also identified tumor‐associated macrophages (TAMs) as the major source of IL‐1β in the MPM microenvironment. Both high mobility group box 1 derived from MPM cells and the asbestos‐activated inflammasome in TAMs induced the production of IL‐1β, which resulted in enhancement of the malignant potential of MPM. We further performed immunohistochemical analysis using clinical MPM samples obtained from patients who were treated with the combination of platinum plus pemetrexed, and found that the overexpression of IL‐1R tended to correlate with poor overall survival. In conclusion, the interaction between MPM cells and TAMs through a IL‐1β/IL‐1R signal could be a promising candidate as the target for novel treatment of MPM (Hyogo College of Medicine clinical trial registration number: 2973). In the present study, we clarified the role of tumor‐associated macrophages (TAMs) in the reinforcement of malignant potential of malignant pleural mesothelioma (MPM) cells. High mobility group box 1 (HMGB1) released from MPM cells (signal 1) induces pro‐interleukin (IL)‐1β production through interactions with Toll‐like receptor 4 (TLR4) in TAMs. In TAMs, phagocytosed asbestos constitutively activates the inflammasome (signal 2), which causes maturation and secretion of IL‐1β. Secreted IL‐1β interacts with the IL‐1 receptor on MPM cells via a paracrine mechanism. Finally, MPM cells acquire a cancer stem cell (CSC)‐like phenotype.