Antigen presenting cells (APC)s of the innate immune response work together with T lymphocytes of the adaptive immune response to generate cellular immunity. APCs process the pathogen/tumor antigens into peptides of 10-20 amino acids while they are in transit to the site of the nearest draining node. At the node, the "processed" antigenic peptides are presented to T lymphocytes by the APCs along with additional activating signals. Once activated, T lymphocytes leave the node and return to the site of pathogen/tumor where they attack cells that express these antigenic peptides. T cells localize to the site of the pathogen/tumor due to the production of APC-derived factors specific to particular sites such as gut and skin. A major goal of this study is to direct tumor specific T cells to a particular site and to provide proof of concept that both antigen and site specific T cell immunity can be produced. Specific aims: Aim 1 will use yeast based immunotherapy approach to determine if the frequency and/or function of CCR9 and CCR10 T cells in various lymphoid tissues correlates with the route of immunization. Aim 2 will determine if frequency and/or function of T cells can be influenced independent of the route of immunization by appropriately modifying the immunotherapy. Aim 3 will determine if this frequency and/or function of T cells can be influenced independent of route even when the draining lymph nodes are dysfunctional or absent. To address the specific aims immunotherapy will be engineered, whole yeast containing antigen, to also produce hormones important for T cell homing - either Vitamin D (skin homing) or Vitamin A (gut homing). Immunization with the immunotherapy containing Vitamin A in the skin and/or Vitamin D in the gut will determine if frequency of antigen specific T cells can be influenced counter to where the antigen was injected. These experiments may "imprint" T cells presented with antigen at the skin to alternatively go to gut, or conversely imprint T cells presented with antigen in the gut to go to skin. While these imprinting experiments have been performed by culturing T cells, DCs and vitamins in vitro this would be a means to avoid these complicated manipulations and induce antigen specific T cell homing entirely in vivo. PUBLIC HEALTH RELEVANCE: The goal is to help the immune system first recognize a tumor as foreign and attack it and second to help the immune system recognize the location of the tumor and direct the bulk of the immune response to the tumor. While currently only gut and skin specific immune response factors are known it is reasonable to assume that other organ specific factors will be discovered. With this in mind we will engineer cancer immunotherapy to any location and aid in tumor regression regardless of location.

F32CA136146

2008-09-01

2009-03-31