Patients with head and neck cancers, most of which are squamous cell carcinomas (HNSCC), have profound defects in their immune defenses. This immune defect is in part due to tumor induction of CD34+ progenitor cells that exhibit natural suppressor (NS) activity in that they inhibit T-cell activation. The hypothesis of the proposed study is that the peripheral blood CD34+ NS cells of HNSCC patients have the potential to differentiate into dendritic cells through several distinct pathways which (a) determine the capacity of the resulting dendritic cells to stimulate T-cell reactivity to cancer, and (b) can be redirected by the tumor to yield dendritic cells with an altered T-cell stimulatory ability. The rationale for this hypothesis is based on our demonstration that (i) CD34+ NS cells of HNSCC patients have the potentiate to differentiate through several different pathways into cells that resemble dendritic cells, and (ii) studies of others showing that dendritic cells derived through various pathways differ in their capacity to stimulate immune reactivity. This hypothesis will be tested through the following Specific Aims: 1. To define if and how peripheral blood CD34+ NS cells of HNSCC patients can differentiate into dendritic cells, and whether the pathways of differentiation can be redirected by HNSCC cancers. 2. To determine if dendritic cells that arise from CD34+ NS cells of HNSCC patients through distinct differentiation pathways differ in their ability to stimulate T-cell reactivity to tumor to tumor, and if HNSCC cancer can redirect differentiation to yield dendritic cells with an altered ability to stimulate T-cells. 3. To determine if human cancers other than HNSCC increase peripheral blood CD34+ cell levels, and if these CD34+ cells can differentiate into dendritic cells. Upon completion, these studies will have determined if it is possible to take advantage of the increased presence of CD34+ NS cells in patients with HNSCC, and very likely other cancers, by directing their differentiation into cells that can stimulate reactivity to autologous cancer.
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