Characterization of post-surgical immunity and memory responses to the poorly-immunogenic B16 melanoma

The potential for the immune system to control growing tumors was recognized over a century ago. Studies during the past 20 years have presented undisputable evidence that host T cells have the ability to recognize, and kill tumor cells. However, despite the presence of T cells that can recognize tumors, clinical response rates of modern immunotherapies have been disappointing. The limited success of immunotherapeutic strategies can be attributed to several factors, but central to this limited success is the fact that cancer arises from normal host cells. Mechanisms of peripheral tolerance preventing immune-mediated damage to normal host tissue must be overcome for successful anti-tumor immunity. Regulatory T cells (Tregs) are key mediators of peripheral tolerance and suppress the priming of T cells against shared tumor/self-antigens and interfering with Treg-cell function results in T cell responses against tumors. However, tumors arise from normal host cells that have acquired mutations, therefore in addition to antigens shared with normal host tissue, tumors also express tumor-specific antigens derived from mutated proteins.;The studies presented here demonstrate that immunotherapies aimed at interfering with Treg-mediated suppression, in contrast to strategies depleting Treg cells, have the potential to selectively drive immune responses restricted against tumor-specific antigens. We find that providing appropriate costimulation to effector T cells results in long-lived post-surgical immunity against the poorly-immunogenic B16 melanoma tumor in the absence of concurrent normal host tissue damage.;Generating robust CD8 memory T cell responses against tumors has remained a challenging goal of anti-tumor immunotherapies and an area of tumor immunology that is poorly understood. We have recently demonstrated that clearing the Treg-cell hurdle by completely depleting Treg cells generates protective post-surgical CD8 memory T cell responses against the poorly-immunogenic B16 melanoma. Treg-cell depletion therapy induces strong anti-tumor immunity, but also results in the development of autoimmune-mediated attack of normal host melanocytes. We find that the development of autoimmunity against host melanocytes correlates with stronger protective CD8 memory T cell responses. In fact, in the absence of autoimmunity, CD8 memory T cells exhibited impaired long-term survival.