Inflammation enhances myeloid-derived suppressor cell cross-talk by signaling through Toll-like receptor 4

Myeloid‐derived suppressor cells (MDSC) are potent inhibitors of anti‐tumor immunity that facilitate tumor progression by blocking the activation of CD4+ and CD8+ T cells and by promoting a type 2 immune response through their production of IL‐10 and down‐regulation of macrophage production of IL‐12. MDSC accumulate in many cancer patients and are a significant impediment to active cancer immunotherapies. Chronic inflammation has been shown recently to enhance the accumulation of MDSC and to increase their suppression of T cells. These findings led us to hypothesize that inflammation contributes to tumor progression through the induction of MDSC, which create a favorable environment for tumor growth. As chronic inflammation also drives type 2 immune responses, which favor tumor growth, we asked if inflammation mediates this effect through MDSC. We find that IL‐1β‐induced inflammation increased IL‐10 production by MDSC and induces MDSC, which are more effective at down‐regulating macrophage production of IL‐12 as compared with MDSC isolated from less‐inflammatory tumor microenvironments, thereby skewing tumor immunity toward a type 2 response. Inflammation heightens MDSC phenotype by signaling through the TLR4 pathway and involves up‐regulation of CD14. Although this pathway is well‐recognized in other myeloid cells, it has not been implicated previously in MDSC function. These studies demonstrate that MDSC are an intermediary through which inflammation promotes type 2 immune responses, and they identify the TLR4 pathway in MDSC as a potential target for down‐regulating immune suppression and promoting anti‐tumor immunity.