Growth hormone secretagogue receptor deficiency promotes lung cancer growth by affecting the Th17/Treg balance

BACKGROUND: Cluster of differentiation 4 (CD4(+)) T cells plays a prominent role in eliminating cancer cells. The balance between T helper (Th)17 and regulatory T (Treg) cells is crucial for optimal immune response and protection against cancer. Growth hormone secretagogue receptor 1a (GHSR1a), a member of the G protein-coupled protein receptor superfamily, plays a critical role in immune cell function. The aim of our study is to investigate the role of GHSR1a in CD4(+) T cell differentiation and lung cancer progression. METHODS: A subcutaneous lung cancer model was used to examine the role of GHSR1a in controlling tumor growth. Lewis lung carcinoma (LLC) cells were subcutaneously implanted into Ghsr1a(−/−) mice and wild-type (WT) mice. The ratio of Th17 and Treg in the draining lymph node of Ghsr1a(−/−) mice and WT tumor-bearing mice was detected by fluorescence-activated cell sorting (FACS). The effect of GHSR1a deficiency on Th17 and Treg cell differentiation was examined using an in vitro differentiation assay. The phosphorylation of mammalian target of rapamycin (mTOR), signal transducer, and activator of transcription (STAT)3 and STAT5 signaling was detected with Western blot. RESULTS: We found that the ablation of GHSR1a resulted in impaired anti-tumor immunity to control lung cancer growth in vivo. We also demonstrated that the deficiency of GHSR1a promoted a shift in the Th17/Treg balance toward enhanced Treg differentiation and inhibited Th17 differentiation both in vivo and in vitro, which suggests that GHSR1a regulates T cell lineage choices between Th17 and Treg cell commitment in the tumor microenvironment. Mechanistically, the deficiency of GHSR1a resulted in reduced phosphorylation in mTOR and STAT3, and increased phosphorylation in STAT5. CONCLUSIONS: Our findings showed the important role of GHSR1a in CD4(+) T cell differentiation in the context of the lung cancer microenvironment. This research provides a novel molecular target and insights into interventions for the prevention and treatment of lung cancer.