Inhibition of Rspo-Lgr4 facilitates checkpoint blockade therapy by switching macrophage polarization

Therapies targeting immune checkpoints have shown great clinical potential in a subset of cancer patients but may be hampered by a failiure to reverse the immunosuppressive tumor microenvironment (TME). As the most abundant immune cells in TME, tumor-associated macrophages (TAM) play non-redundant roles in restricting anti-tumor immunity. The leucine-rich repeat-containing G-protein-coupled receptor 4 (Lgr4, also known as Gpr48) has been associated with multiple physiological and pathological functions. Lgr4 and its ligands R-spondin 1-4 have been shown to promote the growth and metastasis of tumor cells. However, whether Lgr4 can promote tumor progression by regulating the function of immune cells in the tumor microenvironment remains largely unknown. Here we demonstrate that Lgr4 promotes macrophage M2 polarization through Rspo/Lgr4/Erk/Stat3 signaling. Notably, urethane-induced lung carcinogenesis, Lewis Lung carcinoma (LLC,) and B16F10 melanoma tumors were all markedly reduced in Lgr4fl/flLyz2cre/+ mice, characterized by fewer protumoral M2 TAM and increased CD8+ T lymphocyte infiltration in the TME. Furthermore, LLC tumor growth was greatly depressed when Rspo/Lgr4/Erk/Stat3 signaling was blocked with either the LGR4 extracellular domain or an anti-Rspo1 antibody. Importantly, blocking Rspo-Lgr4 signaling overcame LLC resistance to anti-PD-1 therapy and improved the efficacy of PD-1 immunotherapy against B16F10 melanoma, indicating vital roles of Rspo-Lgr4 in host anti-tumor immunity and a potential therapeutic target in cancer immunotherapy.

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