Many tumors are potentially immunogenic, as corroborated by documented in vivo tumor-specific immune responses. Spontaneous clearance of established tumors by endogenous immune mechanisms is rare. Tumor immunotherapy generally mediates poor clinical efficiency. The increasing evidence documented fact that the interaction between tumors and host immune system fosters an immunosuppressive network in the tumor environment. Regulatory T cells (Tregs) actively temper tumor specific immunity and are a significant component of this immunosuppressive network. We studied tumor environmental cells in malignant ascites, tumor and draining lymph nodes of patients with ovarian carcinomas. We demonstrate that in humans with ovarian carcinomas a large amount of tumor environmental CD4+ cells were CD4+CD25+FOXP3+ T cells (CD4+ Tregs). We also demonstrate a suppressive CCR7+CD8+IL-10+ T cell population in ovarian tumor draining lymph nodes and malignant ascites. These T cells are previously-unidentified tumor CD8+ Tregs based on conventional definitions. The origin and functional characteristics of these tumor Tregs are poorly understood. Our central hypothesis is that the pathogenic communication between tumors and hosts contributes to induction, and immune modulation of Tregs, and dysfunctional tumor associated dendritic cell signals contribute to the induction of both types of Tregs. B7-H1 is a novel B7 family member implicated in anergy and tolerance. Ovarian tumors trigger B7-H1 expression on normal peripheral DC and enable DC to induce suppressive T cells in vitro. Thus, we will study how and why tumors condition Treg-inducing DC through distinct mechanisms.
Our specific aims are: 1. Test the hypothesis that tumor contributes to Treg induction. 2. Test the hypothesis that tumor-associated DC induce Tregs. 3. Test the hypothesis that tumor-associated DC induced Tregs are detrimental to tumor immunity. 4. Test the hypothesis that B7 family members are critical for Treg induction. ? ? ?
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