Toll-like receptors (TLRs) are a well-studied class of receptors present on macrophages and dendritic cells, which mediate the recognition and response to foreign pathogens. TLRs recognize distinct pathogen-associated molecular patterns and play a critical role in innate immune responses. They participate in the first line of defense against invading pathogens and play a significant role in inflammation, immune cell regulation, survival, and proliferation.
TLRs are transmembrane proteins that have differential expression on various tissues and cell types. To date, 11 members of the TLR family have been identified, of which TLR1, TLR2, TLR4, TLR5, TLR6, and TLR11 are located on the cell surface and TLR3, TLR7, TLR8, and TLR9 are localized to the endosomal/lysosomal compartment.
TLRs detect pathogens via germ line-encoded pattern recognition receptors, leading to a rapid immune response (within minutes to hours).
These pathogen-associated microbial patterns (PAMPs) are often directed against cell surface and cell wall components of microorganisms, but bacterial DNA containing unmethylated CpG motifs also induce an innate immune response.
Activation of TLRs results in the production of pro-inflammatory and effector cytokines responsible for the immune response.
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It is also well-known that chronic inflammation in the tumor microenvironment has an affect on tumor progression. Stimulation of TLRs on immune cells by damage-associated molecular patterns (DAMPs) expressed by injured or cancerous cells can promote chronic inflammation.
The expression of TLRs has also recently been described in cancer cells, incluidng those from brain, liver, prostate, and ovarian tumors, among others. The activation of TLR signaling on tumor cells has been shown to inhibit apoptosis, promote tumor growth, and build tumor tolerance to host immune responses.
The following table reports a sampling of the reported expression of TLRs on tumors:
|Liver (hepatocellular carcinoma)
|TLR2, 3, 4, 6, 9
|TLR2, 3, 4, 5