Ephrin receptor A10 promotes PD-L1 expression for breast cancer immune evasion

초록

Programmed death-ligand 1(PD-L1) is an immune checkpoint protein and its engagement with programmed cell death protein-1 (PD-1) receptor on T cells activates co-inhibitory signaling to induce cancer immune evasion. PD-L1 or PD-1 blockade has demonstrated encouraging clinical outcomes in several advanced cancer treatment. Elucidating the regulatory mechanisms of PD-L1 is critical to improve the efficiency of PD-L1-targeting immunotherapy. Recent studies indicated that contact-dependent pathways downregulate anticancer immunity, highlighting the importance of cell contact-induced signaling for cancer immune escape. In this study, we show that tumor cell contact promotes PD-L1 expression and reduces immune surveillance via membrane receptor tyrosine kinase ephrin receptor A10 (EphA10), which is only expressed in normal testis tissue and mediates cell contact-dependent juxtacrine signaling. Abolishing the expression of EphA10 enhances T-cell-mediated antitumor immunity in 4T1 mouse model. A positive correlation between EphA10 and PD-L1 expression is observed in human breast cancer tissues. Overall, our findings indicate that cell contact-mediated juxtacrine signaling increases PD-L1 expression, suggesting that tumor cells avoid immune surveillance via this mechanism and blockade of EphA10 may be a new immunotherapy strategy for breast cancer patients.