Mechanisms and consequences of antigen-dependent T cell homing for adoptive immunotherapies

项目总结/文摘

Project Summary/Abstract Adoptive cell therapy (ACT) with activated and expanded T or CAR T cells may be used to treat infections or tumors and ACT with T or CAR T regulatory cells are in clinical trials to control autoimmunity and allograft rejection. Many but not all patients benefit. The success of ACT depends upon T cell homing to relevant tissue sites. Normal circulating T effector memory or T regulatory cells can enter a tissue in response to their cognate antigen being displayed on the surface of the local microvascular ECs in a process triggered by TCR and modulated by costimulation. We hypothesize that antigen presentation by human endothelial cells (ECs) will recruit adoptively transferred in vitro expanded T or CAR T effector and regulatory cells to specific peripheral tissue sites in a process modulated by specific EC co-stimulators. In specific aim 1, we will test this hypothesis in vitro in models we have developed using endothelial cell monolayers in flow chambers to model in vivo conditions. We will expand our in vitro assys to include an examination of the effects that TCR- induced transendothelial migration (TEM) has on the T cells at the single cell level. In the case of CAR T cells, we will determine the most important costimulator receptor molecule motifs to be incorporated into the CAR for optimal TEM. We will also determine if human ECs have the capacity to cross-present or be “cross-dressed” by antigens allowing EC presentation of antigen to influence cancer immunotherapy. Finally, we will use a model we developed for studying adoptively transferred human T cell responses to synthestic microvessels assembled from human ECs, allowing genetic manipulation of the signals human ECs can provide. In aim 2 we will conduct similar experiments using T and CAR T regulatory cells. Successful completion of these aims will provide important information for extending the range of patients who may benefit from ACT.