|Title||Epithelial Mutant p53 Promotes Resistance to Anti-PD-1-Mediated Oral Cancer Immunoprevention in Carcinogen-Induced Mouse Models.|
|Publication Type||Journal Article|
|Year of Publication||2021|
|Authors||Wang J, Hu Y, Escamilla-Rivera V, Gonzalez CL, Tang L, Wang B, El-Naggar AK, Myers JN, Caulin C|
|Date Published||2021 Mar 23|
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 mutations that confer oncogenic gain-of-function (GOF) activities that promote resistance to standard therapies and poor clinical outcomes. To determine whether epithelial mutations modulate anti-PD-1-mediated oral cancer immunoprevention, we generated mouse models for oral carcinogenesis by exposing mice carrying epithelial-specific mutations to the carcinogen 4NQO. Consistent with the oncogenic functions of mutant , mice with OSCCs expressing the GOF mutation developed higher metastasis rates than mice with loss-of-function (LOF) deletion or with wild-type . 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 or deletion, GOF 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 tumors. These findings sustain a potential role for profiling in personalized oral cancer immunoprevention.
|Alternate Journal||Cancers (Basel)|
|PubMed Central ID||PMC8005156|
|Grant List||N/A / / Floyd and Kathleen Cailloux Research Endowment /|
Epithelial Mutant p53 Promotes Resistance to Anti-PD-1-Mediated Oral Cancer Immunoprevention in Carcinogen-Induced Mouse Models.
Carlos Caulin, PhD