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 and accumulation of immature myeloid cells (ImC) able to suppress antigen-specific immune responses. Decreased presence of functionally competent DCs substantially altered the ability of immune system to react to tumor-associated antigens. The mechanisms of the defective DC differentiation in cancer remain unknown. It is known that in healthy individuals differentiation of myeloid cells is taking place in bone marrow, where it is tightly controls by a complex network of cytokines and by direct contact with bone marrow stroma. Transcriptional regulator Notch in HPC and its ligands Jagged and Delta on stromal cells play major role in direct cell-cell contact during cell differentiation in bone marrow. In our preliminary experiments we have discovered that tumor-derived factors induce constitutive activation of JAK/STAT pathway in hematopoietic progenitor cells (HPC). Specifically, it manifested in increased phosphorylation of JAK2 and increased DNA binding of STAT3. In addition, tumor-derived factors downregulate expression of Notch-1 transcriptional regulator. The overall goal of this proposal is to identify mechanisms of the defective myeloid cell differentiation in cancer. To achieve this goal we propose three specific aims:
Specific Aim 1. Investigate the role of JAK/STAT3 in tumor associated defects in DC differentiation.
Specific Aim 2. Investigate the effect of selective Jak2/STAT3 inhibitor JSI-124 on the development of antitumor immune response in tumor-bearing mice.
Specific Aim 3. Investigate the role of transcriptional regulator Notch-1 in DC differentiation.
Specific Aim 4. Study of Notch-1 role in the defective DC differentiation in cancer. In the result of the proposed experiments we hope to be able to establish new molecular mechanisms of the defective myeloid cell differentiation in cancer and to propose new approaches to correct DC defects based on those new mechanisms. ? ?
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