Targeting the Intracellular Domain of PD-L1 to Sensitize Tumors to Cytotoxic Therapy 2085

Abstract Description The PD-L1/PD-1 receptor pathway allows cancer cells to evade immune surveillance, yet only a small percentage of patients benefit from PD-1/PD-L1 inhibitors. This limited efficacy is likely due to gaps in our understanding of PD-1/PD-L1 biology, particularly the lesser-known intracellular roles of PD-L1 compared to its extracellular interactions. Our research found that intracellular PD-L1 functions as an RNA-binding protein, interacting with NBS1 and BRCA1 mRNAs to protect them from degradation, thereby increasing cellular resistance to DNA damage. Given that current PD-1/PD-L1 inhibitors have little effect on intracellular PD-L1, we aimed to develop new drugs targeting this pathway. We created a novel PD-L1 antibody that disrupts the binding of PD-L1 to CMTM6, promoting PD-L1 degradation via the lysosome instead of blocking the PD-1/PD-L1 interaction. This mechanism enables the antibody to inhibit intracellular PD-L1 functions, something conventional immunotherapies cannot achieve. In vivo studies demonstrated that our antibody significantly sensitized tumors to radiation and chemotherapy in patient-derived xenograft models. In a humanized immune-competent triple-negative breast cancer PDX model, it outperformed existing PD-L1 inhibitors, suggesting it enhances anti-tumor immunity through PD-L1 degradation. This novel antibody offers a promising dual approach by targeting both intracellular and extracellular PD-L1, providing a compelling new strategy for cancer therapy. Funding Sources This work was supported in part by the American Society for Radiation Oncology, the National Cancer Institute of the National Institutes of Health under Award Number CA203561, P50CA116201, K12 HD065987, HALT Cancer at X, NCI R21 CA197878 (HD), R01-AI095239 and NIAID R01 AI095239. Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)