Figure 1. Tumor microenvironment: a complex network of intercellular interactions between tumor and inflammatory cells.

Cancer cells in primary tumors are surrounded by a complex microenvironment composed of tumor stroma, blood vessels and infiltrating inflammatory cells. Different types of cells are found in the stroma, including fibroblasts, vascular smooth muscle, epithelial and immune cells. The latter cells comprise effectors of both adaptive immunity, such as T and B lymphocytes, and innate immunity, i.e. macrophages, dendritic cells (DCs), neutrophils, mast cells, eosinophils and natural killer (NK) cells. Most of the stromal cells participate in the promotion of the tumor growth. Cancer associated fibroblasts (CAFs) and M2 like polarized macrophages (tumor associated macrophages: TAMs), which can be induced by tumor-derived factors (for example, TGF-β, FGF or PDGF, among others), support tumor growth, angiogenesis, extracellular matrix remodelling and epithelial mesenchymal transition (EMT), by secreting a plethora of pro-tumorigenic proteases, cytokines and growth factors. For example, EGF, secreted by TAMs, participates in a paracrine signaling loop through tumor-secreted colony stimulating factor (CSF-1). VEGF, CXCL12, IL-8 secreted by CAFs or TAMs interact with their respective receptors expressed by endothelial cells and promote tumor angiogenesis. As tumors grow, immune-suppressor cells, including myeloid derived suppressor cells (MDSC) and T regulatory (T_REG) cells infiltrate the tumor to disrupt immune surveillance through multiple mechanisms, including inhibition of tumor-associated antigen presentation by DCs, T and B cell responses, NK cell cytotoxicity and blockade of M1 macrophage phenotype. Moreover, tumor progression is associated with the increase of TH2 cells secreting immunosuppressive molecules such as IL-4, IL-10 and TGF–β. Mast cells, neutrophils and eosinophils are also recruited to the tumor site where they secrete proliferative and pro-angiogenic factors.