Squamous cell carcinoma (SCC) is the second most common form of skin cancer and is most commonly observed in photo-exposed areas of the body. SCCs localized in the head and/or neck region are often characterized by lymphatic dissemination but the mechanism(s) involved in the progression of this tumor are unknown. Recent studies have shown that there is a direct association between a Th1-related immune response and a better prognosis in patients with SCC. These findings have led us to hypothesize that the protective Th1-type immune response against SCC might be impaired by endogenous immunoregulatory factors. One example is ST2L, which we have recently noted that when it is activated by the cytokine IL-33, Th1-type innate immune responses are impaired. Moreover, ST2L is constitutively expressed on natural killer (NK) cells but its role in these cells during tumor progression remains to be fully elucidated. Based on these findings, we have formulated the hypothesis that immunoregulatory signaling mediated via IL-33/ST2L impairs the Th1-type immune response thereby leaving the development of SCC unchecked. Our three specific aims are as follows: 1. To analyze the development and progression of experimental SCC in ST2 deficient mice or wildtype mice; 2. To analyze the phenotype of inflammatory cells in tumor microenvironment; 3. To analyze the effect of IL-33 on NK cells during experimental SCC.
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