A new PD-L1 antibody H1A causes PD-L1 degradation and sensitizes cancer cells for cytotoxic therapy

Abstract PD-L1/PD-1 receptor pathway represents an important way of cancer cells to escape immune surveillance, yet only small portions of patients can benefit from PD-1/PD-L1 inhibitors. This is at least partially due to incomplete understanding of PD-1/PD-L1 biology in cancer. Although the interaction of extracellular domains between PD-L1 and PD-1 on cancer cells and immune cells is well studied, the function of PD-L1 inside cells, however, has not been well established. In our previous data, we found that intracellular PD-L1 acts as an RNA binding protein and interacts with NBS1 and BRCA1 mRNAs. Furthermore, intracellular PD-L1 protects targeted RNAs from degradation by RNA exosome, therefore increasing cellular resistance to DNA damage. Since Clinical approved PD-1/PD-L1 inhibitors have little effect on intracellular PD-L1, we sought to find new drugs to target intracellular PD-L1. Here we developed a new PD-L1 antibody, H1A, which has a different effect on PD-L1. Instead of blocking of PD-1/PD-L1 interaction, we found that this antibody disrupts the interaction of PD-L1 and CMTM6, which leads to degradation of PD-L1 by the lysosome. Therefore, H1A can unleash host antitumor activity and enhance the effects of DNA damaging therapy in cancer cells at the same time. Indeed, applying H1A in vivosignificantly sensitized tumors to radiation and chemotherapy in a PDX models. Moreover, in a humanized immune competent TNBC PDX model, H1A monotherapy exhibited better therapeutic efficacy compared with clinically available PD-L1 inhibitor, suggesting that H1A activates anti-tumor immunity through PD-L1 degradation. Therefore, H1A may be a potential new drug to target both intracellular and extracellular PD-L1 to improve cancer therapy.