Role of immature myeloid cells in mechanisms of immune evasion in cancer

Abstract

Tumor affects myelopoiesis by inhibiting the process of differentiation/maturation of antigen-presenting cells from their myeloid precursors and by stimulating an accumulation of immature myeloid cells in cancer patients and tumor-bearing mice. These immature myeloid cells can contribute greatly to tumor progression and promote tumor evasion from immune attack: i) by inhibiting development of adaptive immune responses against tumor in lymphoid organs; ii) by migrating into tumor site and differentiating there into highly immune suppressive tumor-associated macrophages. Immature myeloid cells and tumor-associated macrophages utilize different JAK/STAT signaling pathways and different mechanisms to control T cell responses, which include increased production of TGF-beta, reactive oxygen species, peroxynitrites, as well as enhanced L-arginine metabolism. Understanding of precise mechanisms, which tumors use to affect differentiation of APC from myeloid cell precursors and inhibit T cell responses, could help to develop new approaches for cancer therapy and substantially improve efficiency of existing cancer vaccination strategies.

Fig. 1

Contribution of immature myeloid cells to mechanisms of immune evasion in tumor host. Growing tumors affect the process of myeloid cell differentiation and maturation through production of soluble factors. This results in accumulation of immature myeloid cells (iMC) that have increased Stat3 activity, increased ROS production and high MMP-9 expression. These cells migrate in peripheral lymphoid organs and inhibit CD8 T cell immune responses. iMC also can be recruited into tumor site where they differentiate into tumor-associated macrophages (TAM) or endothelial cells. TAM have high Stat1 as well arginase I activities and induce locally T cell apoptosis or anergy