Patients with HIV infection have higher incidence of many cancers and often with a poorer prognosis, despite effective antiretroviral therapy and cancer-targeted therapy. Given that T cell exhaustion has been strongly implicated in cancer incidence and outcome, understanding the connection between chronic, persistent inflammation and T cell dysfunction is critical among patients with HIV who develop cancer. Our preliminary murine data shows that exposure to fatty acids promotes properties of T cell exhaustion (such as increased PD-1 expression and suppression of effector functions). We also find that free fatty acids (FFAs) levels are significantly higher in murine models of chronic viral infection and melanoma compared to healthy controls, two settings in which functionally exhausted PD-1hi T cells are present. Based on these data and preliminary data in HIV infected individuals, we propose that the presence and persistence of lipid dysregulation results in an aggressively pro-inflammatory environment that directly contributes T cell dysfunction and increased PD-1 expression. The high rate of metabolic syndrome among HIV-infected individuals, due to viral infection and antiretroviral therapy itself, further contributes to inflammation and T cell dysfunction. We will thus explore whether there is a direct correlation between lipid dysregulation and T cell exhaustion in HIV-infected patients and whether presence of exhausted T cells results in increased cancer incidence in this population. By utilizing a well-established longitudinal cohort, we are in a unique position to address the role of immune dysfunction and lipid metabolism upon increased cancer incidence among HIV-infected individuals. In addition, we will use both HIV-infected subject samples and a murine model of chronic viral infection to determine the impact of elevated circulating FFA and fatty acid uptake on T cell exhaustion.
Our aims will (1) establish a link between lipid dysregulation and T cell exhaustion in HIV-infected individuals, among HIV- infected individuals who develop cancer, and in tumor tissue from HIV-infected individuals; (2) define the mechanism by which free fatty acid (FFA) uptake, via transporters such as CD36, impacts T cell dysfunction in a murine model of chronic infection, a murine model of cancer, and in HIV-infected individuals; Understanding the inflammatory link between metabolic syndromes and immunosuppressive tumor environment is important to discover new targets to prevent and/or treat cancer, which may include interventions targeting fatty acid signaling.
HIV infection is an independent risk factor for cancer felt to be due to immune activation and immunodeficiency, however, we provide an alternative hypothesis that the increased lipid and metabolic abnormalities found in HIV patients are additional contributing factors. This proposal will intertwine studies on both murine and human T cells to understand how chronic lipid abnormalities associated with chronic viral infection promote T cell dysfunction or ?exhaustion?, which disables one's own immune system from attacking tumors. This work has the potential to reveal new pathways that modulate T cell function and could provide new targets for cancer treatments or prevention.
