Abstract 4979: Multidimensional crosstalk regulates myeloid cell hyperplasia, immune escape, and tumor progression.

Abstract Myeloid-derived suppressor cells (MDSCs) encompass a heterogeneous class of cells in different maturation states that proliferate and accumulate in tumors, secondary lymphoid organs and some epithelial organs during tumor growth. Tumor secretion of growth factors and chemokines regulate myeloid cell proliferation, apoptosis, differentiation, circulation and biodistribution both locally and systemically. There is a reciprocal interaction that occurs between tumor and myeloid cells, which can facilitate tumor growth and metastasis and myeloid cell proliferation and survival via unique and tumor specific arrays of growth factors and chemokines. The tumor microenvironment, a complex, highly dynamic environment composed of host-derived MDSCs, endothelial cells, and fibroblasts; contributes to the microenvironmental crosstalk regulating host immunity and tumor progression. However, the macroenvironment is also a critical to myeloid cell expansion, tumor invasion and immune escape and tumor progression. The primary site of MDSC expansion and immune suppression is splenic extramedullary hematopoiesis, which is regulated by growth factors secreted by the distant primary tumor cells. Similarly, regulation of tumor infiltration by myeloid cells is by tumor secretion of CCL2; however, this occurs at the macroenvironmental level as CCL2/CCR2 blockade inhibits medullary myeloid cell mobilization and recruitment from secondary lymphoid organs and not at the tumor. Further, regulatory crosstalk is bidirectional with tumor-secreted factors differentially upregulating myeloid and lymphoid cell growth factors and enzymes (G-CSF, CXCL1, CCL2, arginase) by medullary myeloid cells and splenic lymphocytes. In tumor bearing, mice the tumor-secreted growth factors support hematopoietic stem/progenitor cell proliferation, limit their apoptosis and inhibit T-cell function. Conversely, leukocyte-secreted cytokines limit immune and hematopoietic growth factor transcript levels by tumor cells (G-CSF, IL-23, CXCL1 and NOS-2) with associated effects on tumor malignancy and leukocyte proliferation and differentiation. In summary, tumors form both local and systemic, bidirectional, regulatory loop(s) between metastatic tumor cells and MDSCs that regulates their proliferation and differentiation supporting tumor metastasis and systemic and regional T-cell suppression. Citation Format: Ibrahim H. Younos, Alicia J. Dafferner, Holly Britton, James E. Talmadge. Multidimensional crosstalk regulates myeloid cell hyperplasia, immune escape, and tumor progression. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4979. doi:10.1158/1538-7445.AM2013-4979