In situ antitumor immunity and effects of radiation

University Of Rochester, Rochester NY

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant):The purpose of this research is to determine how microenvironmental conditions, particularly low oxygen levels, within solid tumors and therapies, such as radiation, alter the interactions that occur between malignant cells and cells of the host immune system. Cytokines produced by host immune cells or used in treatment protocols may greatly alter the tumor microenvironment and the response of malignant cells to subsequent therapy. Using experimental murine tumor models, we have shown that intratumoral production of interleukin-2 (IL-2) not only stimulates T cell mediated immunity, but can also stimulate increased vascularization within the tumors, resulting in enhanced radiosensitivity. In the present proposal we will determine the mechanisms by which IL-2 mediates the increased vascularization and determine whether it is due to direct action on the endothelial cells (EC) or to indirect action via other cells of the immune system. To aid in the identification and isolation of endothelial cells from tumor microcapillary vessels, we will use a unique mouse model whose cells express green fluorescent protein (GFP) and techniques to allow visualization of these structures after minimal manipulation. The vessels will be characterized for their expression of adhesion markers, cytokine and chemokine receptors and compared to vessels from normal organs. Crucial to understanding the immune mechanisms involved in control of tumor growth is additional information on how the microenvironment can influence the availability of tumor antigen to the immune system. The generation of specific T cell mediated immunity requires that antigen presenting cells (APC) such as dendritic cells (DC) migrate into tumors, pick up antigen material, then egress from the tumor to the draining lymph nodes for further maturation and presentation of antigen to naive T cells. Thus, the functional activity of these APC is essential for instigating the first steps in the induction of immunity. Since the trafficking of these cells is via the bloodstream, the experiments to characterize the intratumoral blood vessels will provide essential information for these studies on APC. In this proposal we will study the infiltration, maturation and egress of these essential cells and determine how the tumor microenvironment and radiation alter their trafficking and activity.