One of the reasons for the defects of immune system in cancer is abnormal dendritic cell (DC) differentiation. Tumor growth results in decrease of mature DCs and accumulation of immature myeloid cells, which directly suppress antigen-specific immune responses. However, the molecular mechanisms of the defective DC differentiation in cancer are still unknown. This study is an attempt to clarify them. Our preliminary data have demonstrated possible importance for the defective DC differentiation in cancer of hyper-activation of Jak/STAT pathway in hematopoietic progenitor cells. The overall hypothesis of this proposal is that tumor-derived factors hyper-activate Jak/STAT pathway in hematopoietic progenitor cells or on early stages of myeloid differentiation. This constitutive activation results in defective DC differentiation. To test this hypothesis we will investigate the role of Jak/STAT pathway in tumor-associated defects in DC differentiation in vitro and in vivo. We will also test the hypothesis that block of STAT3 activity will improve DC differentiation and immune response in tumor-bearing mice and antitumor effect of cancer vaccines. Understanding the mechanisms of the defective DC differentiation may lead to the development of new therapeutic approaches aimed on the improvement of immune function in cancer.
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| Nefedova, Yulia; Cheng, Pingyan; Gilkes, Daniele et al. (2005) Activation of dendritic cells via inhibition of Jak2/STAT3 signaling. J Immunol 175:4338-46 |
