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

• Main Authors: Jin Wang, Yuan Hu, Vicente Escamilla-Rivera, Cassandra L. Gonzalez, Lin Tang, Bingbing Wang, Adel K. El-Naggar, Jeffrey N. Myers, Carlos Caulin
• Format: Article
• Language: English
• Published: MDPI AG 2021-03-01
• Series: Cancers
• Subjects: immunoprevention; oral cancer; mutant p53; PD-1; premalignancy
• Online Access: https://www.mdpi.com/2072-6694/13/6/1471

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 <i>p53</i> mutations that confer oncogenic gain-of-function (GOF) activities that promote resistance to standard therapies and poor clinical outcomes. To determine whether epithelial <i>p53</i> mutations modulate anti-PD-1-mediated oral cancer immunoprevention, we generated mouse models for oral carcinogenesis by exposing mice carrying epithelial-specific <i>p53</i> mutations to the carcinogen 4NQO. Consistent with the oncogenic functions of mutant <i>p53</i>, mice with OSCCs expressing the <i>p53^R172H</i> GOF mutation developed higher metastasis rates than mice with loss-of-function (LOF) <i>p53</i> deletion or with wild-type <i>p53</i>. 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 <i>p53</i> or <i>p53</i> deletion, GOF <i>p53^R172H</i> 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 <i>p53^R172H</i> tumors. These findings sustain a potential role for <i>p53</i> profiling in personalized oral cancer immunoprevention.