UC Irvine

Basal cell carcinoma (BCC) is the most common cancer in the US, but treatment of advanced tumors becomes complicated by drug resistance. Current targeted therapies for advanced BCC suppress inappropriate activation of the Hedgehog signaling pathway and result in potent tumor regression. Yet, they are only effective in 40% of the tumors, with 20% of the initial responders acquiring resistance to these drugs within one year. Therefore, there is an urgent need for alternative methods to treat advanced BCCs and possibly halt tumor development before they reach later stages. This thesis work investigates different mechanisms of modulating BCC tumor growth and progression to understand the mechanisms in the skin environment that dictate whether these tumors will form or regress. Understanding what dictates tumor progression versus intrinsic tumor control holds the potential to enable the development of novel and combination treatment strategies for BCC patients. We used a transgenic BCC mouse model that grows microtumors that spontaneously regress over time to study the role of immune system interactions in promoting tumor regression in BCC. The study aims to define the immune response against BCC tumors and determine the regulatory role of effector lymphocytes in regression. We use this inducible transgenic model coupled with varying degrees of immune cell perturbations, including genetic knockout of lymphocytes and antibody depletions of cell subtypes, to determine the effect on tumor burden. Single-cell RNA sequencing and immunofluorescence microscopy reveal an upregulated innate immunity cytokine response and a T cell Th1-driven response. The CellChat algorithm for inference of communication probability in single-cell data reveals IFNγ and CCL5 signaling from T cells to BCC cells, neutrophils, macrophages, or other T cells. There is also evidence of immune regulation by lymphocytes in the BCC tumor microenvironment, as lack of αβ T cells and adaptive immunity impairs efficient tumor growth (p<0.05) and increases immune infiltration. This work suggests that effector lymphocytes exhibit cytotoxicity in BCC microtumor regression, but the major immune response is pro-tumoral during tumor growth. Primary cilia loss is a common feature of advanced cancers. While primary cilia are necessary to initiate Hedgehog-driven cancers, how Hedgehog (HH) pathway activity is maintained in advanced cancers devoid of primary cilia is unclear. Loss of Alström and Usher syndrome gene expression suppresses ciliogenesis and HH signaling, leading to the accumulation of mutations in advanced and Smoothened (SMO) inhibitor- resistant tumors. Atypical protein kinase C iota/lambda (aPKC) is a GLI1 kinase with higher expression in advanced BCCs and can drive HH pathway activity and mutually antagonize primary cilia. We use novel BCC models that express aPKC to gain critical insight into how aPKC impacts the ability of tumors to grow and the relationship with cilia. Elucidating the precise role of aPKC in BCC progression provides a better understanding of its therapeutic implications in BCC treatment. Together, these findings could help develop more effective and personalized treatments for varying degrees of BCC tumor growth and progression.