Figure 5.

Myeloid cell recruitment to tumors by multiple mechanisms. Chemoattractants produced within the TME recruit and retain myeloid cells, which are indispensable for tumor growth and development. Tumor cells, tumor-associated macrophages (TAMs), and cancer-associated fibroblasts (CAFs) secrete myeloid cell-attracting chemokines such as CCL2, CXCL1/2, and CXCL8. Recruited myeloid cells are reprogramed to support the entirety of tumorigenesis, from tumor initiation and growth to invasion and metastasis. Endothelial cells also produce chemokines and/or display them on glycocalyx that they have on the luminal side. Some tumor types express complement C3 and C5. Their cleaved forms, C3a and C5a, are potent chemoattractants of myeloid cells which express receptors for C3a and C5a (C3aR and C5aR). Leukotrienes (LTs) are critical signaling mediators in mammalian biology. They also play significant roles in the immune system, including cancer immunity. While leukotriene-metabolism is present in a range of cell types, myeloid cells are the major producer of leukotrienes in the TME. Some cancer cells can also generate a large amount of LTs. LT receptors such as BLT1 are expressed broadly in myeloid immune cells and LT binding to their receptors induces adhesion and chemotactic migration of neutrophils, monocytes and macrophages. Hypoxic conditions are inevitable in solid tumors and are an obstacle for growing tumors. However, successful tumors adapt themselves to hypoxia, inducing neovascularization and using it as a tool for immune evasion. Tumor cells and TAMs in hypoxic conditions attract and retain myeloid immune cells by enhanced expression of chemokines, then those recruited myeloid cells facilitate angiogenesis by providing proangiogenic growth factors and MMPs. Myeloid cells under hypoxia are reprogramed toward an immunosuppressive phenotype through anti-inflammatory cytokines including IL-10. VEGF, a critical factor for angiogenesis which is elevated significantly under hypoxia, is also a myeloid cell attractant. TME also has high levels of damage-associated molecular patterns (DAMPs) including High mobility group box 1 (HMGB1) and extracellular nucleotides/nucleosides. DAMPs are secreted passively upon cell death or actively released under stress conditions. Secreted HMGB1 has multiple inflammatory functions including immune cell recruitment. Tissues under inflammatory and cancerous conditions are rich in ATP, which is actively released from cells through specialized plasma membrane channels such as PANX-1. ATP is a strong stimulator of both fast cell migration (mediated by PANX-1/P2X7R complex) and direct chemotaxis of immune cells. ATP can be rapidly metabolized to adenosine by ectonucleotidases including CD39 and CD73, then adenosine induces chemotactic migration and immunosuppression of innate immune cells. Tumor endothelial cells (TECs) are unique structurally and functionally. In hepatocellular carcinoma, VEGF from the TME generates TECs and the TECs are an immune-signaling hub that recruits MDSCs and Tregs.