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

PD-1
metalloproteinases NOS-2: Nitric Oxide Synthase
Blood vessel VEGF MDSC Ang-1: Angiopoietin-1 PD-1: Programmed Death-1

MMP9
ARG-1: Arginase-1 PDGF: Platelet Derived Growth

Treg TIM3 Bcl2: B cell lymphoma 2 Factor

NO IL-10 bFGF: basic Fibroblast Growth RANTES: Regulated upon activation

TGF-β TGF-β CD4+ CTLA-4 CAFs:

factor
Cancer Associated
normal T cell expressed and
secreted
CTLA-4
EGFL7 IL-10 Th1
Fibroblasts RCAS-1: Receptor binding cancer
CSF-1: Colony Stimulating Factor-1 antigen expressed on SiSo
TGF-β IFN-γ TIM3 PD-1 CTL: Cytotoxic T Lymphocyte cells
ARG-1 CTLA4: Cytotoxic T Lymphocyte
Antigen 4
SCF: Stem Cell Factor
SDF-1: Stromal Cell-Derived
NOS-2 IL-10 IFN-γ
CTLA-4
DAMPS: Damage Associated Factor-1

TGF-β
Molecular Patterns SIRP-α: Signal-regulatory Protein
VCAM TGF-β ECM: Extracellular Matrix alpha
IL-10 EGF: Epidermal Growth Factor SPI-6: Serine Protease Inhibitor-6
Egfl7: Epidermal Growth Factor TAMs: Tumor Associated
like domain 7 Macrophages
VEGF IL-10 CSF-1
ICAM: Intracellular Adhesion TGF-β: Transforming Growth Factor
Cytolytic Molecule beta
Bcl2 IL-6 IDO: Indoleamine 2,3 Th1: T Helper 1
granules IFN-γ dioxygenase TIM3: T cell Immunoglobulin and

Pericytes CD4 +
IL-17 CD8+ IFN-γ: Interferon Gamma Mucin domain-containing
DAMPS IL: Interleukin molecule-3

ICAM Dendritic IDO Th17 RCAS-1 NK CTL MCP: Monocyte Chemoattractant

Protein
TIMPs: Tissue inhibitors of
metalloproteinases
SPI-6 MICA NKG2
cells
MDSC: Myeloid Derived Suppressor Treg: Regulatory T cells
Cells uPA: Urokinase-type Plasminogen
MICA: Major histocompatibility Activator
complex class I-related chain VCAM: Vascular Cell Adhesion

TAMs FasL A Molecule

MMPs: Matrix Metalloproteinases VEGF: Vascular Endothelial Growth
TGF-β NK: Natural Killer Factor
MMP12 CD47 soluble FasL Exosomes
PDGF
NKG2: Natural Killer Group 2

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
P-selectin EGF
generate both tumor enhancing and suppressing signals. CAF’s and myofibroblasts are stromal cells that
are abnormal, but not malignant, and promote angiogenesis and 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
CSF-1 tumor growth through a paracrine manner. TGF-β causes activation of fibroblasts while PDGF recruits fibroblasts and
MMP 3, 7, 9, 16 induces proliferation. VEGF does not directly recruit fibroblasts, but indirectly supports microenvironmental changes
TGF-β via the regulation of the vascular network. Proteins 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
E-selectin function to balance the protease activity of MMP’s to shift the balance from a pro-angiogenic to an inhibitory
environment.
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
MMP’s 1, 2, 3, 9, 11 cells, Th1 CD4+ T cells and CD8+ CTLs secreting IFN-Y and releasing
cytolytic granules is required for effective killing of tumor cells.
Cathepsin’s B, L, S, K
Fibroblasts
However, many obstacles stand in the way of immune
ADAM’s 10, 17 mediated tumor cell killing, including regulatory T
cells, MDSC, tumor derived exosomes, inhibitory
TIMPs molecules including MICA, CD47, RCAS-1, PD-L1,
SPI-6 and immunosuppressive cytokines such
as IL-10 and TGF-β.
SDF-1 Proteoglycan
MMP2, 9 www.abcam.com
TGF-β Arginase
VEGF
SDF-1 CXCR4 Laminin
CXCR4
RANTES
Fibronectin
Galectins 1,2,3 and 9 SCF
Arginase
Laminin
Key MMP-3 VEGF
Ang-1 CXCR4
Secretes 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

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