Figure 2.

Damage-associated molecular pattern molecules in the tumor microenvironment. HMGB1 has a dual effect on tumors. Acute release of HMGB1 after antitumor treatments promotes maturation of DCs through interaction with TLR4 and clonal expansion of tumor antigen-specific T cells and antitumor responses. Conversely, persistent hypoxia in growing tumors leads to necrosis, causing chronic release of HMGB1, which activates protumor responses promoting angiogenesis and tumor growth through the recruitment of macrophages (TAM) and endothelial precursor cells (EPC) and activation of local endothelial cells through RAGE signaling. In the bone marrow, S100A8/A9 are downregulated during normal differentiation of myeloid precursors to DC and macrophages. However, tumor-derived factors promote sustained up-regulation of S100A9 in myeloid precursors through a STAT3 dependent process, which results in the inhibition ofDCdifferentiation and accumulation of MDSC. S100A8/A9 are synthesized and secreted by MDSC and bind carboxylated glycans on other MDSC. This promotes migration and accumulation of MDSC in blood and peripheral lymphoid organs, possibly through RAGE- and NF-κB-dependent pathways, thereby establishing an autocrine feedback loop that maintains MDSC levels and promoting immune suppression against tumors. S100A8/A9 promote tumor growth through RAGE- and carboxylated glycan-dependent pathways. Tumor-derived factors also induce expression of S100A8/A9 inmyeloid and endothelial cells in premetastatic niches within lungs, which promotes homing of tumor cells to lungs.