Cutaneous squamous cell carcinoma (cSCC) manifests through the complex interactions of UV-induced DNA damage, genetic mutations, and alterations in the tumor microenvironment. A high mutational burden is present in cSCC, as well as both cSCC precursors and normal skin, making driver genes difficult to differentiate. Despite this, several key driver genes have been identified, including TP53, the NOTCH family, CDKN2A, PIK3CA, and EGFR. In addition to mutations, the tumor microenvironment and the manipulation and evasion of the immune system play a critical role in cSCC progression. Novel therapeutic approaches, such as immunotherapy and EGFR inhibitors, have been used to target these dysregulations, and have shown promise in treating advanced cSCC cases, emphasizing the need for targeted interventions considering both genetic and microenvironmental factors for improved patient outcomes.

Background/Objectives: Non-melanoma skin cancer, which includes cutaneous squamous cell carcinoma (cSCC), ranks as the 5th most common cancer globally with high morbidity and more total deaths than melanoma despite having a lower mortality rate. While most cSCC cases can be treated with surgery, locally advanced, metastatic, and high-risk cSCC tumors are associated with a worse prognosis with higher rates of recurrence and require multimodality therapy. However, there is limited data on animal models of cutaneous squamous cell carcinoma for the use of combinatory immunotherapy and radiation. Methods: In this study, spontaneously generated tumors using DMBA/TPA were treated over three weeks with either IgG control, anti-PD1 antibody monotherapy, 8 Gy of localized radiation, or a combination of anti-PD1 and 8 Gy of radiation followed by anti-PD1 therapy. Results: We found that while anti-PD1 therapy showed a trend toward slowed tumor growth compared to controls, this difference was not statistically significant (p = 0.0775), with most mice showing continued tumor progression. Preliminary histological analysis suggested that anti-PD1 treatment increased CD8+ T cell infiltration, and the addition of radiation further enhanced CD8+ responses but added greater variability. A pathologic review revealed that irradiated tumors were associated with fibroblastic spindle-like cell morphology. Conclusions: This animal model represents a potential preclinical model for studying CSCC with limited responses to immunotherapy to understand potential mechanisms of resistance.