Immunoregulation of the Pulmonary Environment by Non-Hematopoietic Stromal Cells

描述(申请人提供)：免疫疗法在实体肿瘤的治疗中仅显示出有限的成功。这种失败的一个主要原因是存在正常的外周耐受诱导机制，这种机制在正常情况下起到防止自身免疫性疾病发生的作用。然而，在免疫治疗过程中，这些过程也会阻碍肿瘤排斥反应。我们发现，肺非造血基质细胞上主要组织相容性II类分子(MHCII)的表达在下调炎症反应中起着关键作用，包括那些阻止转移肿瘤生长的炎症反应。这项应用的总体目标是确定表达MHCII的非造血基质细胞用于防止肿瘤排斥反应的机制，并探索下调MHCII作为一种基于免疫的治疗方法的可能性。我们在三个非相互排斥的目标中探索了CD4+Foxp3+调节性T细胞在控制炎症变化中的作用，T细胞在抑制肿瘤血管生成中的功能，以及shRNA介导的MHCII下调作为一种治疗方式的可能性。

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.