Knockdown (KD) of RSPO3, LGR4 or their signaling mediator IQGAP1 in lung cancer cell lines with Keap1 deficiency and high RSPO3-LGR4 expression led to reduction in cell proliferation and migration in vitro, and KD of LGR4 or IQGAP1 resulted in decrease in tumor growth and metastasis in vivo.
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 antitumor immunity and a potential therapeutic target in cancer immunotherapy.<b>Significance:</b> This study identifies a novel receptor as a critical switch in TAM polarization whose inhibition sensitizes checkpoint therapy-resistant lung cancer to anti-PD-1 therapy.<b>Graphical Abstract:</b> http://cancerres.aacrjournals.org/content/canres/78/17/4929/F1.large.jpg <i></i>.