| dc.description.abstract | The high incidence of local recurrence in oral squamous cell carcinoma (OSCC) is linked to an immunosuppressive microenvironment. Macrophages play a pivotal role in remodeling tumor immunity. Leukemia inhibitory factor (LIF) is a pleiotropic cytokine with functions associated with tumor progression. Nevertheless, whether LIF modulates the functions of macrophages and hence induces a tumor-promoting microenvironment remains to be explored. In this study, we aimed to investigate the role of LIF in regulating function of macrophages and to determine the clinical relevance between LIF and macrophage-mediated immunity within OSCC. By analyzing the TCGA-OSCC database, we found higher levels of LIF and M2-like macrophage markers (CD206, CD163, VEGF) in tumor samples compared to normal counterparts. An elevated LIF expression was further correlated with a poorer overall survival (p =0.0019). Immunohistological analysis on OSCC revealed that macrophages were predominantly localized at the periphery of tumors infiltrated with LIF-rich immune cells. On the other hand, macrophages with a larger phenotype were found in the core area of tumors, in which the LIF immunoreactivities were negative to weak in immune populations. Treatment of recombinant LIF (rLIF) induced an immunosuppressive polarization, which was supported by increased expression of M2-like markers (CD163 and CD209) and decreased levels of M1-like markers (iNOS and CD86). In a macrophage-cancer cell coculture system, rLIF treatment promoted the motility and proliferation of OSCC cells, whereas decreased cytotoxic abilities of macrophages. Treating macrophages with soluble LIF receptor (sLIFR), a LIF antagonist, partly reversed the rLIF-mediated M2-like polarization and decreased cancer cytotoxicity. Results of single-cell RNA sequencing on rLIF-treated OSCC biopsy revealed suppression of antigen presentation process in macrophages, which was further verified by quantitative real-time polymerase chain reaction. Further, rLIF treatment in macrophages resulted in suppressed functions on type I interferon production, TNFR, and Hippo-YAP signalings. Mechanistically, rLIF-induced M2- like polarization may be promoted through YAP1 activation, which was evident by an enhanced YAP1 nuclear translocation and increased expressions of active YAP1 and its downstream proteins (CTGF, IGFBP3, and PDGFR⍺β). Pharmaceutical inhibition of YAP1 reduced the rLIF-mediated immune responses in macrophages. Collectively, our findings shed light on the LIF-mediated effects on macrophages. We proposed that LIF assists in establishing an immune- suppressive and tumor-promoting microenvironment through activating YAP1 in OSCC. Blockade of LIF-mediated effects might have the potential of converting the immunosuppressive microenvironment for selected OSCC patients. | en_US |