Identification of S1PR4 as an immune modulator for favorable prognosis in HNSCC through unbiased machine learning

As the largest family of membrane proteins, G protein-coupled receptor (GPCR) has become the most prominent family of pharmacological targets. Whereas, only a little GPCRs have been well defined in physiological and pathological functions. Thus, an efficient way to identify key GPCRs in tumor formation is urgent needed. Here, the head and neck squamous cell carcinoma (HNSCC) patients were classified into two identical subtypes by the characteristics of GPCR with unbiased machine learning method. Interestingly, these two subtypes showed significant differences in prognosis, gene expression, and immune microenvironment, especially the infiltration of CD8+ T cell. Based on these differences, we screened three potential key regulators (S1PR4, S1PR5, and GPR87) from all GPCRs, and constructed a prognosis-predicting nomogram for HNSCC patients. Further, we identified S1PR4 as the key GPCR in determining the two subtypes for positively correlated with both proportion and cytotoxicity of CD8+ T cells in HNSCC, and was mainly expressed in a subset of CX3CR1+CD8+ T cells. Moreover, we also demonstrated S1PR4 as an immune modulator for favorable prognosis of HNSCC patients. We found that S1PR4 was highly expressed in CD8+ T cells from the tumor of HNSCC patients which was greatly associated with better prognosis, and S1PR4 expressing accompanied with higher T cell cytotoxic markers expression (IFNG and GZMB). Most importantly, S1PR4 was co-localization with CX3CR1, which has been identified as the most cytotoxic marker of CD8+ T cell. Taken together, these results identified S1PR4 as a key indicator for cytotoxicity and proportion of tumor infiltrating CD8+ T cells, and confirmed the prognostic value of S1PR4 in HNSCC. Our findings contributed to the knowledge of S1PR4 in anti-tumor immunity, providing a potential GPCR-targeted therapeutic option for future HNSCC treatment.