The Role of the Microenvironment and Th17 cells in the Carcinogenesis of Head and Neck Squamous Cell Carcinoma

Head and neck cancer is the sixth most common cancer worldwide. Despite advances in diagnosis and treatment, the survival rates for patients with head and neck cancer have remained relatively unchanged for the past 30 years. Head and Neck Squamous Cell Carcinoma is a highly aggressive malignancy with a 5-year survival rate of only 50%. Of the patients diagnosed every year, 5% of head and neck squamous cell carcinoma (HNSCC) patients develop additional primary tumors, an effect that is thought to be associated with the high degree of immune suppression induced by the tumor. During the premalignant stage of HNSCC, there is an increase in the number of helper T subset Th17 cells, which then decreases in fully established HNSCC. The focus of our laboratory is on delineating the role of Th17 cells in HNSCC tumor development. Thus, the goal of this study is to elucidate the role of the tumor microenvironment in the decrease in Th17 cells observed in established HNSCC. We hypothesize that the decrease in Th17 cells is due to changes that occur in the tumor microenvironment during the transition from premalignant tissue to established HNSCC. To examine this, we characterized the cytokine levels in normal, premalignant and HNSCC tongue tissues. We also investigated the role of the microenvironment in the decrease in Th17 cell numbers observed in fully developed HNSCC compared to the premalignant stages. Our data showed an inflammatory response at the microenvironment which included both an increase in inflammatory cytokines as well as an increase in Th17 cells. This response was later attenuated during the HNSCC stage. When incubated with supernatant from premalignant tissue, Th17 cells maintained a higher level of IL-17 when compared to incubating with supernatant from control or HNSCC tissue. The opposite was found when splenocytes were incubated with these same supematants. The levels of IL-17 dropped when incubated with supernatant from premalignant tissue when compared to control or HNSCC

The C3H/HeJ inbred mouse is a model of vesico-ureteric reflux with a susceptibility locus on chromosome 12

Vesico-ureteric reflux is the most common congenital anomaly of the urinary tract, characterized by a defective uretero-vesical junction with retrograde urine flow from the bladder toward the kidneys. Because there is strong evidence for a genetic basis for some cases of vesico-ureteric reflux, we screened 11 inbred mouse strains for reflux and kidney size and identified one strain, C3H/HeJ, that has a 100 percent incidence of vesico-ureteric reflux with otherwise normal kidneys at birth. These mice are predisposed to reflux as a result of a defective uretero-vesical junction characterized by a short intravesical ureter. This defect results from a delay in urinary tract development initially manifested by a ureteric bud arising from a more caudal location along the mesonephric duct. In contrast, C57BL/6J mice (resistant to reflux at birth) have long intravesical ureters, normally positioned ureteric buds, and no delay in urinary tract development. Genome-wide and additional fine mapping of backcross mice, derived from C3H/HeJ and C57BL/6J crosses, identified a significant reflux susceptibility locus, Vurm1, on chromosome 12 (peak logarithm of the odds=7.39). The C3H/HeJ mouse is a model of vesico-ureteric reflux without renal malformation, and further characterization of this model will allow for the identification of a pathway important for urinary tract development, a finding that will serve as a model for the human disorder