Understanding How Different Populations of Tumor Initiating Cells Contribute to the Tumor Immune Microenvironment

In the skin mutations in the C-Ha-Ras gene are critical initiating events in the genesis of squamous cancers. The classical 2-stage model of skin carcinogenesis and many other studies illuminate the tumor promoting role of inflammation in this cancer model as well as other cancers in humans. To investigate mechanisms through which oncogenic Ras promotes an inflammatory environment in the skin we have developed two epidermally targeted transgenic models that allow regulated induction of oncogenic Ras in either the basal/stem cell proliferative or suprabasal post-mitotic differentiated compartments of the epidermis. Our studies show that expression of Ras in both models generates inflammation but that the nature of the inflammatory response is significantly different. High level expression of RAS in the suprabasal layer generates a hyperproliferative hyperkeratotic psoraisiform epidermis characterized by a cytotoxic intraepidermal neutrophilic infiltrate. This infiltrate is dependent on IFNγ expressing CD8+ T cells. In contrast, acute basal/stem cell expression of RAS causes the rapid generation of myeloid derived suppressor cells (MDSC) without evidence of an intraepidermal infiltrate, and this phenotype is dependent on B cells. Surprisingly, removal of the adaptive immune system has opposite effects on tumor formation in the basal and suprabasal Ras models. Our current studies are focused on understanding the role of B cells in generating the MDSC phenotype and determining the mechanism by which distinct signals are transmitted to the immune system by neoplastic cells dependent on their location in the differentiation hierarchy.