Abstract A14: The p53R172H gain-of-function mutation promotes resistance to oral cancer immunoprevention

Abstract

Abstract Oral squamous cell carcinomas (OSCC) tend to develop from oral premalignant lesions (OPLs) through the accumulation of genetic alterations. Therefore, effective prevention strategies designed to block the malignant progression of OPLs are expected to contain the development of aggressive carcinomas. Our previous studies showed that immune checkpoint blockade can prevent the progression of OPLs to OSCC, in a mouse model for oral carcinogenesis. However, a subset of the lesions continued to progress even after treatment with anti-PD1 antibodies. Mutations that accumulate in the epithelial cells of the oral lesions may shape the immune microenvironment of the oral lesions and impact the response to immunotherapies. The p53 gene (TP53) is the most frequently mutated gene in OSCCs, as over 80% of the OSCCs contain p53 mutations. Most p53 mutations found in human cancers are missense mutations that encode mutant forms of p53, some of which are associated with poor clinical outcomes and can transform cells as a result of their gain-of-function (GOF) activities. To assess the role of p53 mutations in the response to anti-PD-1 immunoprevention, we generated mouse models in which oral tumors were induced by the carcinogen 4NQO in genetically engineered mice in which the p53 GOF mutation p53R172H or deletion of p53, a loss-of-function (LOF) mutation, were activated in oral epithelial cells. Therefore, the OPLs that developed in these mice differed in their p53 status. We found that the oral lesions that developed in these mice showed a gradual increase in T-cell infiltration during oral cancer progression, the recruitment of immunosuppressive regulatory T-cells (Tregs), and induction of PD-1/PD-L1 immune checkpoint proteins. Remarkably, while PD-1 blockade prevented the development of SCCs in mice with wild-type p53 or p53 deletion, the GOF mutant p53R172H abrogated the immunopreventive effects of anti-PD-1 antibodies, associated with depletion of exhausted CD8 cells in the microenvironment of the p53R172H tumors. Overall, these findings indicate that mutant p53R172H promotes the development of an immune microenvironment that prevents the efficacy of PD-1 inhibitors. These studies suggest that p53 profiling may help to predict the response to oral cancer immunoprevention, and patients with OPLs containing wild-type p53 or p53 LOF mutations may benefit from the immunopreventive effects of anti-PD1 antibodies. Citation Format: Jin Wang, Yuan Hu, Cassandra Gonzalez, Lin Tang, Bingbing Wang, Adel El-Naggar, Jeffrey Myers, Carlos Caulin. The p53R172H gain-of-function mutation promotes resistance to oral cancer immunoprevention [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; 2019 Apr 29-30; Austin, TX. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_2):Abstract nr A14.