The Stabilization Of Pd-L1 By The Endoplasmic Reticulum Stress Protein Grp78 In Triple-Negative Breast Cancer

The immune checkpoint blockade therapy has emerged as encouraging treatment strategies in various cancer types. Anti-PD-L1 (programmed death ligand 1) antibodies have been approved for triple negative breast cancer, however the response rate yet to be optimized. It would be imperative to further understand and investigate the molecular mechanisms of PD-L1 regulation. Here, we identified glucose regulatory protein 78 (GRP78), a major endoplasmic reticulum (ER) stress responding protein, as a novel binding partner of PD-L1. GRP78 interacts with PD-L1 at the ER region and increases PD-L1 levels via regulating its stability. ER stress, triggered by different stimuli such as conventional chemotherapy, leads to the induction of PD-L1 in a GRP78-dependent manner. We showed that GRP78 modulates the response to chemotherapy, and dual high levels of GRP78 and PD-L1 correlates with poor relapse-free survival in triple negative breast cancer. Altogether, our study provides novel molecular insights into the regulatory mechanism of PD-L1 by revealing its interaction with GRP78, and offers a rationale to target GRP78 as a potential therapeutic strategy to enhance anti-tumor immunity.