Cutaneous squamous cell carcinoma (cSCC) is one of the most common human cancers with increasing incidence and a high risk of mortality globally. UV radiation and immunosuppression are important risk factors of SCC. For instance, immune-compromised patients display increased incidence of SCC with an estimated increase in risk of ~50-100-fold compared to immune-competent individuals. In addition, chronic UV exposure is immune suppressive, leading to induction of T regulatory cells and antigen-presenting cells suppression. These strongly support immunotherapy developing for advanced cSCC, other than surgery and combined chemo-radiotherapy, of which the overall responses are often unsatisfactory and poor, primarily due to local recurrences. The Wells lab has discovered that CD8+ T-cells critically determine whether SCCs will establish and grow, or whether SCCs will regress and perish. However, the attributes of CD8+ T-cells that promote these tumor fates, and how they can be manipulated to provide better treatments for patients, are completely unknown. It has been shown previously that IFN-regulated genes are upregulated in SCC lesions compared to basal cell carcinoma lesions, and this is associated with T-cell infiltration and recruitment of CXCR3+ effector cells [1]. These observations pinpoint the importance of IFN-associated host responses, including the CXCR3 pathway for effector cell recruitment in tumor immune-surveillance in the skin. In our lab, we have generated a mouse SCC cell line derived from UV-irradiated HPV38 E6/E7 FVB mice. Interestingly, we are able to control the SCC-tumor growth/regression using T-cell targeted immunosuppressants, tacrolimus (TAC) or rapamycin (RAPA), administered with the diet. Preliminary data using this model showed that CXCR3 blockade prevented progression of established SCC tumors compared to isotype control group. This model will allow me to define the relevance of CXCR3 and IFN-γ pathways in the establishment and regression of SCC tumors and the CD8+ T-cells subsets responsible of these phenotypes.