fig2

Figure 2. The complex interactions among the cell types composing TRS in CCA. In cholangiocarcinoma, neoplastic cells (CCA) are at the center of a complex interplay with a number of cell types that infiltrate the tumor microenvironment (TME) and a strongly modified extracellular matrix (ECM). Inflammatory cells and cancer-associated fibroblasts (CAFs), residing in close vicinity to CCA, can influence each other through the secretion of soluble mediators. CCA cells are able to recruit CAFs by secreting platelet-derived growth factor (PDGF)-D, transforming growth factor (TGF) β, and fibroblast growth factor (FGF); natural killer (NK) cells via the C-X-C motif ligand (CXCL) 9 - C-X-C motif chemokine receptor (CXCR) 3 axis; and cancer-associated macrophages (TAMs) through IL-6, IL-13, IL-34, TGFβ, and osteoactivin. In turn, these cells exert a trophic effect on neoplastic cells by secretion of soluble mediators. CAFs are also actively involved in the recruitment of lymphatic vessels and in the modifications of the ECM by secreting metalloproteinases (MMPs)-1, -2, -3, and -9, collagens, and other structural proteins such as osteopontin (OPN), tenascin C (TnC), and periostin (POSTN). The TME is also the site of an intense modulation of the innate and adaptive immune responses. Immune cells recruited into the tumor reactive stroma (TRS) influence each other in a difficult balance between immune surveillance and immune tolerance. Dendritic cells (DCs) stimulate the activation of tumor-infiltrating lymphocytes (TILs), while tumor-associated macrophages (TAMs) actively recruit tumor-associated neutrophils (TANs). Conversely, myeloid-derived suppressor cells (MDSC) inhibit the activity of immune cells, such as TILs, TANs, and NKs. The ability of each cancer to respond to immune therapy depends on the balance between these factors and the adaptation of the TME. Association of different targets (immune checkpoints and/or signaling targets) may be a pathway to therapeutic success.