Ingenuity

Pathway
Analysis

Sample to Insight

Tumor Microenvironment Pathway

from QIAGEN® Ingenuity® Pathway Analysis (IPA®)

The shapes represent molecules. The nodes are color-coded

according to the inference that they are inhibited (green) or
activated (red) when the pathway is activated.

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Tumors use various means to redirect elements of the immune system to encourage proliferation and suppress
immune attack. This molecular activity is illustrated in this pathway (see back for detailed description), and in
the related PD-1, PD-L1 cancer immunotherapy pathway from QIAGEN IPA (not shown).
Tumor Microenvironment Pathway
The tumor microenvironment (TME) comprises cancer cells,
the cytokine environment, extracellular matrix, immune cell
subsets and other components. In this complex network, the
pro-tumorigenic immune response, mediated by diverse
immunosuppressive cell signaling molecules, plays a pivotal
role in driving immune evasion. The tumor not only manages to
escape from the host immune system, but it effectively benefits
from infiltrating cells by modifying their functions to create the
microenvironment favorable for tumor progression (1).
The majority of stromal cells within the TME are specific fibroblasts
with a myofibroblastic phenotype and are distinguished
as cancer-associated fibroblasts (CAFs). These CAFs have
a significant impact on cancer progression through remodeling
the ECM, inducing angiogenesis, recruiting inflammatory
cells, and directly stimulating cancer cell proliferation via
the secretion of growth factors, intermediate metabolites and
immune-suppressive cytokines (2).
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous
population of immature myeloid cells possibly derived from
neutrophils attracted to tumors (3), which are expanded
in pathological conditions and up-regulate the expression of
immune suppressive factors, such as arginase and inducible
nitric oxide synthase (NOS2), thus reducing lymphocyte
functions. MDSCs also show high expression of indoleamine
2,3-dioxygenase (IDO), an enzyme responsible for the
catabolism of tryptophan, which leads to inhibition of T cell
proliferation and induces T cell apoptosis. Local hypoxia has
been identified as another key regulator that can promote
MDSC accumulation (4).
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The cancer cell-derived cytokines, such as IL-4, IL-13,
CSF1, CCL2, induce tumor-associated macrophage (TAM)
differentiation. These secrete multiple key proinflammatory
cytokines (e.g., IL-1β, IL-6, and TNF-α), which stimulate
tumor progression and in parallel inhibit lymphocyte functions
through the secretion of IL-10, and also contribute to the
expansion of Th17 cells, which induce local inflammation. TAMs
also produce vascular endothelial growth factor (VEGF), which
stimulates tumor angiogenesis, promoting its invasiveness and
metastatic potential (1).
Tumor-associated neutrophils (TANs) are associated with
aggressive cancer phenotypes, facilitate angiogenesis, promote
mutagenesis and suppress the immune system. The migration
of TANs from the blood circulation into the TME is stimulated
by tumor-derived CXCL8. TANs mainly suppress anti-tumor
immunity via interacting with CD8+ T cells, inducing their
apoptosis through nitric oxide production (4).
References
1. Fu, Y. et al. (2019) From bench to bed: the tumor immune
microenvironment and current immunotherapeutic
strategies for hepatocellular carcinoma. J Exp Clin Cancer
Res. 38(1):396.
2. Wang, M. et al. (2017) Role of tumor microenvironment in
tumorigenesis. J Cancer 8(5):761.
3. Zhou, J. et al. (2018) Neutrophils and PMN-MDSC: Their
biological role and interaction with stromal cells. Semin
Immunol. 35:19.
4. Barriga, V. et al. (2019) The complex interaction between
the tumor microenvironment and immune checkpoints in
breast cancer. Cancers (Basel) 11(8):1205.