Tumor Microenvironment: Immunosuppressive Cells

Many cell types are thought to contribute to the generation of an immunosuppressive tumor microenvironment (TME) including cancer-associated fibroblasts, myeloid-derived suppressor cells, regulatory T cells, and tumor-associated macrophages. Read below for a brief description of each cell type and the mechanisms by which they contribute to immune suppression. Click the links to browse our offering of relevant proteins, antibodies, ELISAs, kits, and small molecules.

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Cancer-associated Fibroblasts (CAFs)

CAFs, which can be identified by expression of the membrane protein Fibroblast Activation Protein alpha/FAP, suppress anti-tumor immune responses by restricting T cells to the stroma and preventing them from accumulating in the vicinity of cancer cells by at least two mechanisms:

Production of dense extracellular matrix (ECM)
- The dense ECM traps T cells in the stroma, denying them access to cancer cells.
Secretion of CXCL12
- CAF-secreted CXCL12 coats T cells and excludes them in a CXCR4-dependent manner.

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Tumor-associated Macrophages (TAMs)

TAMs are involved in tumor-promoting angiogenesis, fibrous stroma deposition, and metastasis formation. Both M1- and M2-polarized macrophages have been identified in the TME. The mechanisms by which TAMs induce immune suppression are not completely understood, but they likely involve the following:

TGF-beta production
- TGF-beta negatively regulates effector T cell (Teff) function and induces Treg differentiation and maintenance.
VEGF and CCL18 production
- VEGF and CCL18 secreted by TAMs promote angiogenesis and tumor progression.

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Myeloid-derived Suppressor Cells (MDSCs)

MDSCs are a heterogenous population of immature myeloid progenitor cells that fail to differentiate into granulocytes, macrophages, and dendritic cells. MDSCs display immunosuppressive properties that are thought to create or contribute to the immunosuppressive TME. MDSC-mediated immune suppressive mechanisms include:

Production of Arginase 1/ARG1 and upregulation of iNOS
- ARG1 and iNOS metabolize L-arginine and cause the loss of the TCR zeta chain, promote nitration or nitrosylation of TCR, CD3, CD8, and CCL2, disrupt IL-2 signaling, and inhibit T cell proliferation.
Secretion of immunosuppressive cytokines
- Secretion of IL-10 and TGF-beta leads to the induction of regulatory T cells and the inhibition of NK cell and CD8+ T cell functions.

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Regulatory T Cells (Tregs)

Tregs are a heterogeneous subset of CD4+ T cells with suppressive properties that play a central role in maintaining immune homeostasis and self-tolerance, dampening inflammation, and preventing autoimmunity. Tregs also represent a significant suppressive population in tumors and they function by inhibiting the activities of CD4⁺ and CD8⁺ effector T cells, natural killer cells, NKT cells, and antigen-presenting cells through multiple mechanisms including:

Secretion of immunosuppressive cytokines
- Secretion of TGF-beta 1, IL-10, IL-35, and Galectin-1 inhibits differentiation, proliferation, and activation of Teff cells, and suppresses cytokine production by Teff cells. IL-35 and TGF-beta 1 induce IL-10 production and regulate FoxP3 expression, promoting the maintenance and expansion of CD4+CD25+ Treg cells.
Production of cytolytic factors
- Secretion of Granzyme A/Granzyme B induces apoptosis in dendritic cells and Teff cells in both a perforin-dependent and -independent manner.