An immunosuppressive tumor microenvironment (TME) is able to preferentially restrict accumulation of T cells in the vicinity of cancer cells. Several mechanisms by which the TME can exclude T cells have been described and are outlined below, but a better understanding of these mechanisms is needed. The potential clinical efficacy of therapeutic strategies that target T cell exclusion mechanisms also needs to be assessed. Click the links to browse our offering of relevant proteins, antibodies, ELISAs, kits, and small molecules.
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)
- Immunosuppression – the dense ECM traps T cells in the stroma, denying them access to cancer cells.
- Potential therapeutic strategy - Both collagenase and CCL5 have been shown to increase T cell movement out of stromal regions and into the vicinity of cancer cells.
- Secretion of CXCL12
- Immunosuppression – CAF-secreted CXCL12 coats T cells and excludes them in a CXCR4-dependent manner.
- Potential therapeutic strategy – CXCR4 inhibitors increase T cell numbers in the vicinity of cancer cells and improve efficacy of anti-PD-L1 antibody treatment.
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Detection of FAP in Human Basal Cell Carcinoma by IHC
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Reactive Nitrogen Species
Reactive nitrogen species can induce the nitration of proteins. This post-translational modification has a wide range of functional consequences depending on the protein modified. The production of reactive nitrogen species by myeloid-derived suppressor cells (MDSCs) within the TME leads to T cell exclusion.
- Nitration of CCL2
- Immunosuppression – CCL2 nitration results in the trapping of T cells in the stroma surrounding tumor cells.
- Potential therapeutic strategy – Inhibition of CCL2 nitration has been shown to enhance the accumulation of tumor-infiltrating lymphocytes (TILs) and improve efficacy of adoptive T cell therapy.
The tumor vasculature is involved in the preferential recruitment of other immune cells in place of effector T cells to the tumor microenvironment. Multiple mechanisms by which the tumor vasculature can override the effects of chemotactic signals for T cell extravasation and recruitment to the tumor have been described.
- Fas Ligand/TNFSF6 expression
- VEGF and B7-H3 or EDNRB/Endothelin R Type B
- Immunosuppression – Decreased T cell infiltration and worse clinical outcome have been correlated with elevated VEGF levels along with expression of either B7-H3 or EDNRB/ETBR on tumor vessels.
- Potential therapeutic strategy – Treatment with EDNRB/ETBR inhibitors inhibitors inhibitors increased T cell adhesion to endothelial cells, which resulted in elevated TILs and an anti-tumor response to an otherwise ineffective anticancer vaccine. Inhibitors of VEGF and VEGF R2 also increase TILs and improve immunotherapy efficacy. TNF-alpha treatment has been reported to normalize blood vessels and increase CD8+ T cell infiltration and efficacy of ACT.
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Neutralization of B7-H3-induced Proliferation using a B7-H3 Antibody
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Axitinib: Potent VEGF R1, -2, and -3 Inhibitor