Immunoregulation of the Pulmonary Environment by Non-Hematopoietic Stromal Cells

Washington University, Saint Louis MO

Investigators

Abstract

DESCRIPTION (provided by applicant): Immunotherapy has shown only limited success in the treatment of solid tumors. A major reason for such failure is the existence of normal mechanisms for peripheral tolerance induction, which function under normal circumstances to prevent the onset of autoimmune disease. However, these processes also hinder tumor rejection during immunotherapy. We have discovered that the expression of major histocompatibility class II molecules (MHCII) on non-hematopoietic stromal cells in the lung plays a critical role in downregulating inflammatory responses, including those that prevent the growth of metastatic tumors. The overall goal of this application is to determine the mechanisms utilized by MHCII expressing non-hematopoietic stromal cells to prevent tumor rejection as well as to explore the possibility of downregulating MHCII as a method of immune- based therapy. We explore, in three non-mutually exclusive aims, the role of CD4+Foxp3+ regulatory T cells in controlling inflammatory changes, the function of T cells in inhibiting tumor angiogenesis, and the potential for shRNA-mediated downregulation of MHCII as a therapeutic modality.