Lgr4 deficiency attenuates tumor formation by reprograming macrophage polarization in lung cancer (TUM6P.973)

Abstract

Abstract Macrophage polarization is increasingly recognized as an important pathogenetic factor in tumor formation. Our previous study has shown that Lgr4 negatively regulates TLR2/4 associated pattern recognition in innate immune responses. However, the exact roles and mechanisms of Lgr4 in macrophage polarization remain largely unknown. Here, we found that patients with Lgr4-high lung cancers displayed much poorer survival than the rest of the cohorts. Meanwhile, Lgr4 is also aberrantly expressed at high levels in macrophages from clinical lung adenocarcinomas (ADs), implying the potential role of Lgr4 in tumor-associated macrophages (TAMs). In addition, the expression of Lgr4 in bone marrow derived macrophages (BMMs) was reduced by IFN-γ and increased by IL-4 significantly. Interestingly, Lgr4 deficiency BMMs showed a obviously increased M1 phenotypes and reduced M2 phenotypes. Accordingly, host deficiency in Lgr4 resulted in defective and reduced growth of subcutaneously implanted Lewis lung carcinoma (LLC). Consistent with the defective growth, LLC cells implanted into Lgr4 conditional knockout mice also displayed reduced TAMs and increased M1 like macrophages in tumor tissues, suggesting impaired TAMs polarization. These findings suggest that deletion of Lgr4 may inhibits tumor growth via reprograming TAMs polarization. Thus, Lgr4 expressed in TAMs may potentially become a novel target for cancer therapy.