G Protein-Coupled Receptor 56 Characterizes CTLs and Reflects the Progression of Lung Cancer Patients

CTLs play important roles in host immune responses to tumors. CD4 CTLs are characterized by their ability to secrete cytotoxic effector molecules, such as granzyme B and perforin, and kill target cells in a MHC class II-restricted manner. However, the cell surface markers of CD4 CTLs remain unknown, which hinders their separation and research on their function. In this study, we performed a bioinformatics analysis and experimental validation that revealed that G protein-coupled receptor 56 (GPR56) is a cell surface marker that can be used to characterize CD4 CTLs. We found that GPR56 and granzyme B were coexpressed in extremely high levels in human peripheral blood T cells, and that anti-GPR56 stimulation significantly upregulated the expression of granzyme B in both CD4(+)GPR56(+) and CD8(+)GPR56(+) T cells. These findings suggest that GPR56 expression and the GPR56 signaling pathway could contribute directly to the toxic function of either CD4(+) or CD8(+) T cells. We also used GPR56 as a biomarker to investigate the clinical significance of CD4 CTLs. GPR56(+) T cell levels were increased in patients with lung cancer, and GPR56 expression was significantly correlated with lung cancer progression. A further analysis revealed an increase in exhausted cell states in lung cancer patients because of upregulation of programmed cell death protein 1 expression in GPR56(+) T cells. The findings of this study suggest that GPR56 characterizes the cytotoxic states of either CD4(+) or CD8(+) T cells.