Head and neck squamous cell carcinoma (HNSCC) is marked by immunosuppression, a state in which the established tumor escapes immune attack. However, the impact of the premalignant and tumor microenvironments on immune reactivity has yet to be elucidated. The purpose of this study was to determine how soluble mediators from cells established from carcinogen-induced oral premalignant lesions and HNSCC modulate immune cell cytokine production. It was found that premalignant cells secrete significantly increased levels of G-CSF, RANTES, MCP-1, and PGE₂ compared to HNSCC cells. Splenocytes incubated with premalignant supernatant secreted significantly increased levels of Th1-, Th2-, and Th17-associated cytokines compared to splenocytes incubated with HNSCC supernatant. These studies demonstrate that whereas the premalignant microenvironment elicits proinflammatory cytokine production, the tumor microenvironment is significantly less immune stimulatory and may contribute to immunosuppression in established HNSCC.

Differences in levels of inflammation-modulating cytokines and adipokines in patients with premalignant oral lesions versus in patients that develop squamous cell carcinoma of the head and neck (HNSCC) were assessed. Also assessed was the impact of treating HNSCC patients with the immune regulatory mediator, 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3], on modulators of inflammation. Compared to healthy controls, patients with premalignant oral lesions had increases in their systemic levels of the inflammatory cytokines IL-6 and IL-17, and increases in the adipokine, leptin. However, levels of these pro-inflammatory cytokines and adipokine were reduced in patients with HNSCC. Treatment of HNSCC patients with 1,25(OH)2D3 increased levels of each of the measured immune mediators. Levels of the anti-inflammatory adipokine, adiponectin, were shifted inversely with the levels of the pro-inflammatory cytokines and with leptin. These studies demonstrate heightened immune reactivity in patients with premalignant lesions, which wanes in patients with HNSCC, but which is restored by treatment with 1,25(OH)2D3.

Post-traumatic stress disorder (PTSD) is a disabling psychological disorder characterized by chronic symptoms of intrusiveness, avoidance, and hyperarousal after a traumatic event. Retrospective studies have indicated PTSD increases the risk for cardiovascular disease (CVD) including arrhythmia, hypertension, and myocardial infarction. The goal of this study was to: 1) use a murine model of cued fear conditioning (inescapable foot shock, IFS) to develop a scoring method to distinguish a PTSD-like phenotype, and 2) use this model system to characterize the cardiac phenotype and function in mice with extreme PTSD-like behaviors. We compared 3 groups, controls, non-responders (NR), and PTSD-like mice at 2 time points [4-weeks and 8-weeks post-IFS] to compare left ventricular structure and function. Assessment of cardiac function showed both male and female PTSD-like mice had increased isovolumetric relaxation time at 8-weeks post-IFS, whereas only females demonstrated increases in E/e', left atrial diameter, and decreased ejection fraction compared to control mice. Female PTSD-like mice also demonstrated increased interstitial fibrosis through picrosirius red staining and increased expression of fibrotic genes including Col3a1 and Lox. Overall, our data indicated that mice displaying behavioral characteristics associated with PTSD present with sex-dependent diastolic dysfunction likely due, at least in part, to an activation of cardiac fibrosis.