Epithelial Mutant p53 Promotes Resistance to Anti-PD-1-Mediated Oral Cancer Immunoprevention in Carcinogen-Induced Mouse Models

Simple Summary Immune checkpoint blockade with anti-PD-1 antibodies blocks the development of oral squamous cell carcinomas (OSCCs) in preclinical models. Understanding whether the genetic alterations that accumulate during oral cancer development affect the response to PD-1 inhibitors is critical to identify patients who may benefit from immunoprevention interventions. Using genetically engineered mouse models that develop carcinogen-induced oral tumors that differ on the mutational status of the p53 gene, we demonstrated that expression of gain-of-function mutant p53 in the epithelial cells of the oral lesions promotes resistance to the immunopreventive effects of anti-PD-1. These novel findings could guide patient-specific strategies for oral cancer immunoprevention based on p53 profiling. Oral squamous cell carcinoma (OSCC) develops through the multistep malignant progression of squamous epithelium. This process can be prevented by PD-1 blockade in a mouse model for oral carcinogenesis. OSCCs exhibit a high incidence of p53 mutations that confer oncogenic gain-of-function (GOF) activities that promote resistance to standard therapies and poor clinical outcomes. To determine whether epithelial p53 mutations modulate anti-PD-1-mediated oral cancer immunoprevention, we generated mouse models for oral carcinogenesis by exposing mice carrying epithelial-specific p53 mutations to the carcinogen 4NQO. Consistent with the oncogenic functions of mutant p53, mice with OSCCs expressing the p53(R172H) GOF mutation developed higher metastasis rates than mice with loss-of-function (LOF) p53 deletion or with wild-type p53. Throughout oral cancer progression, pre-invasive and invasive lesions showed a gradual increase in T-cell infiltration, recruitment of immunosuppressive regulatory T-cells (Tregs), and induction of PD-1/PD-L1 immune checkpoint proteins. Notably, while PD-1 blockade prevented the development of OSCCs in mice with wild-type p53 or p53 deletion, GOF p53(R172H) abrogated the immunopreventive effects of anti-PD-1, associated with upregulation of IL17 signaling and depletion of exhausted CD8 cells in the microenvironment of the p53(R172H) tumors. These findings sustain a potential role for p53 profiling in personalized oral cancer immunoprevention.