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 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 immunotherapy. 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. In the proposed clinical trial we will test the hypothesis that ATRA eliminates immature myeloid cells and improves differentiation of DC in cancer patients. If proven this approach can be used to enhance the effects of cancer vaccines. ? ? ?
| Mirza, Noweeda; Fishman, Mayer; Fricke, Ingo et al. (2006) All-trans-retinoic acid improves differentiation of myeloid cells and immune response in cancer patients. Cancer Res 66:9299-307 |
