Endogenous PD-L1-Blocking Antibodies Drive Potent Anti-Tumor Immunity

Checkpoint blockade therapy, though transformative, remains ineffective in 70-80% of patients, with autoimmune adverse effects. Here, we provide the first evidence of a naturally occurring form of immune checkpoint blockade mediated by endogenous antibodies that functionally replicate the effects of therapeutic checkpoint inhibitors, without autoimmune symptoms. Through cloning and reconstructing patient-derived monoclonal antibodies, we show that certain cancer patients produce PD-L1-blocking antibodies that can restore T cell function and induce potent anti-tumor immunity. Broad polyreactive responses to multiple checkpoints confer no survival advantage. However, patients who are selectively positive for PD-L1 antibodies exhibit prolonged survival, tumors enriched with memory T cells, and activated circulating T cells. Mechanistically, these PD-L1 antibodies block PD-1/PD-L1 interactions and restore T cell function, in vitro and in vivo, revealing a naturally regulated form of checkpoint inhibition. Our data reveal that key principles of successful immunotherapy can emerge endogenously in a subset of patients, redefining our understanding of immune competence, tolerance, and therapeutic responsiveness in cancer, offering a mechanistic framework to explain how certain patients mount more effective anti-tumor immunity. This dataset contains the transcriptomic data of 2,946 B cells originated from the study.