EXCEED THE SPACE PROVIDED. Inability of host immune system to develop and maintain antitumor immune response is one of the mechanisms of tumor progression. We have previously described a new mechanism of immune deficiency in cancer associated with defective differentiation of dendritic cells (DC). These findings were confirmed in many laboratories. Defective DC differentiation is mediated by tumor-derived factors and manifests in decreased production of the mature DCs. Decreased presence of functionally competent DCs substantially altered the ability of immune system to react to tumor associated antigens. Recently we have found that decreased DC production in cancer patients and tumor-bearing mice is associated with striking accumulation of immature myeloid cells (ImC). This effect is not restricted to a certain type of cancer. To date studies from different laboratories demonstrated increased production of these cells in patients with all tested types of cancer and in all tested tumor animal models. ImC actively suppress antigen-specific immune response in tumor-bearing hosts. These cells may play a critical role in tumor non-responsiveness. They may compromise attempts to immunotherapy of cancer, since administration of tumor-specific antigens to the patients will make these antigens available for ImC. ImC would inhibit the very same immune response that immunization is trying to generate. It appears, that elimination of ImC by therapeutic intervention may be one of the possible ways to improve the immune response in cancer and the efficiency of cancer immunothcrapy. Our preliminary data have demonstrated that differentiation of ImC could be the most effective way to eliminate these cells and all-trans-retinoic acid (ATRA) could be one of the most attractive candidates. The mechanisms of ImC inhibition of T-cell responses remain unclear. Elucidation of these mechanisms can be important for our better understanding of tumor immunology as well as for development of new therapeutics. In this proposal we tried to achieve two major goals: 1) to understand the mechanisms of ImC function and 2) to identify the effective methods of elimination of ImC in tumor-bearing hosts. To achieve these goals I propose the following specific aims:
Specific Aim 1. Identify the mechanisms of antigen presentation and T-cell inhibition by immature myeloid cells generated in tumor-bearing hosts.
Specific Aim 2. Determine mechanisms of ImC development in tumor-bearing hosts.
Specific Aim 3. Identify the effect of ATRA on the development of antitumor immune response in tumor-bearing mice PERFORMANCE SITE ========================================Section End===========================================
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