Potentiated effects of lactate receptor GPR81 on immune microenvironment in breast cancer

Abstract G protein‐coupled receptor (GPR81), as lactate receptor, is an upstart in immune regulation, however, its mechanisms involved in tumor escape have not been fully elucidated. In this study, we explored the effects of GPR81 activation on triple‐negative breast cancer (TNBC) cells and macrophages. The expression and relationship with immune infiltration of GPR81 were analyzed with TCGA database. Checkpoints and cytokines were evaluated with flow cytometry or ELISA. The TCGA‐based data showed a marked decrease of GPR81 in breast cancer (BRCA) compared with normal breast, especially in the basal‐like subtype. In normal mammary tissues, GPR81 had negative correlation with various immune checkpoints, nevertheless, this trend weakened accompanied with the reduction of GPR81. GPR81 stimulation had a significantly inhibitory influence on PD‐L1 exposure in BT‐549 and MDA‐MB‐231 cell lines, but not in MDA‐MB‐453 cell line. The pretreatment of siGPR81 to knockdown GPR81 expression resulted in a remitting of PD‐L1 reduction when MDA‐MB‐231 cells were treated with GPR81 agonist 1. However, little effect of GPR81 activation was observed on the expression of PD‐L1 on phorbol‐12‐myristate‐13‐acetate (PMA)‐induced THP‐1 cells. Furthermore, GPR81 agonist 1 exerted no significant impact on the secretion of cytokines in THP‐1 cells. In general, it is suggested that GPR81 may facilitate immune monitoring via the reduction of PD‐L1 in TNBC with glycolytic phenotype. Our results not only provide a novel insight into the effects of GPR81 on immune evasion but a potential therapy targeting GPR81 in BRCA.