Cross-Talk Between Tumor Microenvironment and the Immune System by Dr

Cross-talk between tumor microenvironment and the immune system by Dr. Jacintha O’Sullivan and Dr. Joanne Lysaght, Trinity College Dublin and Abcam

Abbreviations ADAM’s: A disintegrin and NO: Nitric Oxide metalloproteinases NOS-2: Nitric Oxide Synthase Ang-1: Angiopoietin-1 PD-1: Programmed Death-1 PD-1 ARG-1: Arginase-1 PDGF: Platelet Derived Growth Blood vessel VEGF MDSC Bcl2: B cell lymphoma 2 Factor MMP9 bFGF: basic Fibroblast Growth RANTES: Regulated upon activation TIM3 factor normal T cell expressed and IL-10 Treg CAFs: Cancer Associated secreted NO + TGF-β CD4 Fibroblasts RCAS-1: Receptor binding cancer TGF-β CTLA-4 CTLA-4 CSF-1: Colony Stimulating Factor-1 antigen expressed on SiSo EGFL7 IL-10 CTL: Cytotoxic T Lymphocyte cells Th1 CTLA4: Cytotoxic T Lymphocyte SCF: Stem Cell Factor TGF-β IFN-γ TIM3 PD-1 Antigen 4 SDF-1: Stromal Cell-Derived ARG-1 DAMPS: Damage Associated Factor-1 NOS-2 IL-10 Molecular Patterns SIRP-α: Signal-regulatory Protein CTLA-4 IFN-γ ECM: Extracellular Matrix alpha TGF-β TGF-β EGF: Epidermal Growth Factor SPI-6: Serine Protease Inhibitor-6 VCAM Egfl7: Epidermal Growth Factor TAMs: Tumor Associated IL-10 like domain 7 Macrophages ICAM: Intracellular Adhesion TGF-β: Transforming Growth Factor Molecule beta VEGF IL-10 IDO: Indoleamine 2,3 Th1: T Helper 1 CSF-1 Cytolytic Bcl2 IL-6 dioxygenase TIM3: T cell Immunoglobulin and granules IFN-γ: Interferon Gamma Mucin domain-containing IFN-γ + IL: Interleukin molecule-3 Pericytes + IL-17 CD8 MCP: Monocyte TIMPs: Tissue inhibitors of DAMPS CD4 Chemoattractant Protein metalloproteinases ICAM CTL MDSC: Myeloid Derived Suppressor Treg: Regulatory T cells Dendritic IDO Th17 RCAS-1 NK Cells uPA: Urokinase-type SPI-6 MICA NKG2 MICA: Major histocompatibility Plasminogen Activator cells complex class I-related VCAM: Vascular Cell Adhesion chain A Molecule FasL MMPs: Matrix Metalloproteinases VEGF: Vascular Endothelial TAMs NK: Natural Killer Growth Factor TGF-β NKG2: Natural Killer Group 2 Exosomes PDGF MMP12 CD47 soluble FasL VEGF bFGF PD-L1 SIRPα The tumor microenvironment affects angiogenesis by interfering with signaling pathways required for vascular construction. The absence of normal vasculature causes a physical constraint on the microenvironment. Tumors recruit endothelial cells, fibroblasts inflammatory cells and pericytes, and these with components of the ECM contribute to the microenvironment composition. Stromal cells generate both tumor enhancing and suppressing signals. CAF’s and myofibroblasts are stromal cells that are abnormal, but not malignant, and promote angiogenesis and P-selectin EGF proliferation. These fibroblasts secrete growth factors and cytokines that produce oncogenic signals. Activated fibroblasts promote angiogenesis via expression of SDF-1. Tumor cells also express CXCR4, the receptor for SDF-1 and stromal SDF-1 can stimulate tumor growth through a paracrine manner. TGF-β causes CSF-1 activation of fibroblasts while PDGF recruits fibroblasts and induces proliferation. VEGF does not directly recruit MMP 3, 7, 9, 16 fibroblasts, but indirectly supports microenvironmental changes via the regulation of the vascular network. Proteins TGF-β secreted by the tumor modify the microenvironment by inducing growth factors and proteases that degrade the ECM, and affect cell motility and adhesion. Stromal cells secrete ECM proteins, cytokines, growth factors, proteases and protease inhibitors. TIMP’s are endogenous inhibitors of MMP’s and function to balance the protease activity of MMP’s to shift the balance from a pro-angiogenic to an inhibitory environment. E-selectin An anti-tumor immune response begins as a result of local tissue damage due to the expanding tumor and the release of “danger signals” from dead or dying tumor cells. A mature dendritic cell will present acquired tumor antigens to T cells in sentinel lymph nodes. A pro-inflammatory cell mediated immune response with NK cells, Th1 CD4+ T cells and CD8+ CTLs secreting IFN-Y and releasing cytolytic granules is required for effective killing of tumor cells. However, many MMP’s 1, 2, 3, 9, 11 obstacles stand in the way of immune mediated tumor cell Cathepsin’s B, L, S, K killing, including regulatory T cells, MDSC, tumor derived Fibroblasts exosomes, inhibitory molecules including MICA, CD47, ADAM’s 10, 17 RCAS-1, PD-L1, SPI-6 and immunosuppressive TIMPs cytokines such as IL-10 and TGF-β. www.abcam.com SDF-1 MMP2, 9 Proteoglycan TGF-β VEGF Arginase Laminin SDF-1 CXCR4 CXCR4 RANTES Fibronectin Galectins 1,2,3 and 9 SCF Arginase Laminin ey MMP-3 VEGF CXCR4 Secretes Ang-1 Proteoglycan uPA bFGF Neutrophils (N2) Inhibits secretion IL-8 MMP9 or expression MCP-1 Proteases Fibronectin Induces function Mast cells Inhibits function Extracellular matrix Collagen