Abstract 537: Preclinical PD-1 resistance models: Crucial tools for unveiling PD-1 resistance mechanisms and advancing novel treatment strategies

Abstract In the cancer-immunity cycle, the immune checkpoint PD-1 and its ligand PD-L1 collaborate to facilitate tumor immune evasion and promote tumor progression by thwarting immunity-induced apoptosis. Immune checkpoint inhibitors disrupt this alliance by preventing PD-1 from binding to PD-L1, thereby reactivating the patient's immune system. While anti-PD-1/PD-L1 therapy has demonstrated remarkable efficacy in treating solid tumors, durable responses are observed in only a minority of patients. The majority of patients do not experience the full benefits of anti-PD-1/PD-L1 therapy, and a significant proportion of initial responders eventually develop acquired resistance. Thus, the establishment of reliable preclinical PD-1 resistance models is of paramount importance for uncovering resistance mechanisms and devising novel treatment strategies. Common mechanisms contributing to PD-1/PD-L1 resistance include the absence of appropriate tumor antigens, inactivation of tumor surface MHC molecules, aberrant IFNγ signaling pathways, and the presence of an immunosuppressive tumor microenvironment. We have successfully generated multiple drug resistance models at both cellular and animal levels, offering valuable tools for the investigation of diverse drug resistance mechanisms. For instance, our animal model of drug resistance, induced by long-term treatment with the PD-1 antibody (Keytruda), simulates the clinical scenario of acquired resistance due to prolonged medication. Through gene editing techniques, we have created a drug-resistant cell line (CT26-B2M KO) by disrupting the B2M gene in the CT26 cell line, thereby mimicking a tumor model with B2M functional deficiency in mice. Additionally, we have compiled efficacy data from various naturally occurring resistant models, which serve as valuable resources for studying primary resistance or intricate resistance mechanisms. In summary, preclinical PD-1 resistance models serve as crucial tools for researchers to dissect the intricacies of PD-1 resistance mechanisms and offer essential guidance for the development of innovative treatment strategies. Citation Format: Yini Zhu, Yuan Fang, Huiyi Wang, Jun Xing, Lu Yang, Jing Zhao, Xiang Gao, Cunxiang Ju. Preclinical PD-1 resistance models: Crucial tools for unveiling PD-1 resistance mechanisms and advancing novel treatment strategies abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 537.