Abstract
Toll-like receptor 2 (TLR2) expressed on myeloid cells mediates the recognition of harmful molecules belonging to invading pathogens or host damaged tissues, leading to inflammation. For this ability to activate immune responses, TLR2 has been considered a player in anti-cancer immunity. Therefore, TLR2 agonists have been used as adjuvants for anti-cancer immunotherapies. However, TLR2 is also expressed on neoplastic cells from different malignancies and promotes their proliferation through activation of the myeloid differentiation primary response protein 88 (MyD88)/nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) pathway. Furthermore, its activation on regulatory immune cells may contribute to the generation of an immunosuppressive microenvironment and of the pre-metastatic niche, promoting cancer progression. Thus, TLR2 represents a double-edge sword, whose role in cancer needs to be carefully understood for the setup of effective therapies. In this review, we discuss the divergent effects induced by TLR2 activation in different immune cell populations, cancer cells, and cancer stem cells. Moreover, we analyze the stimuli that lead to its activation in the tumor microenvironment, addressing the role of danger, pathogen, and microbiota-associated molecular patterns and their modulation during cancer treatments. This information will contribute to the scientific debate on the use of TLR2 agonists or antagonists in cancer treatment and pave the way for new therapeutic avenues.
Highlights
The immune system provides a complex cellular and molecular protection from pathogen infection
The role played by Toll-like receptor 2 (TLR2) in this complex interaction is ambivalent, since its ability to activate protective immune responses is counterbalanced by its immunosuppressive and pro-tumoral effects, which have prevented the diffusion of its agonists as anti-cancer drugs
We are firmly convinced that a deeper understanding of the multifaceted activity played by TLR2 in cancer cells, immune cells, and in the tumor microenvironment (TME) could lead to strong improvements in medical oncology, posing the foundations for the development of new combined anti-cancer treatments
Summary
The immune system provides a complex cellular and molecular protection from pathogen infection. PRRs are transmembrane proteins associated to the cellular and endosomal membranes or the cytosol They recognize molecules frequently associated with pathogens, the so-called pathogen-associated molecular patterns (PAMPs), leading to activation of downstream signal transduction pathways, which result in the production of inflammatory cytokines, type I interferons (IFNs), and other mediators. These processes trigger inflammation and regulate antigen-specific adaptive immune responses, and they are essential for the clearance of infecting microbes [10]. A deeper comprehension of these two mechanisms is essential for the development of new approaches for the design of anti-cancer therapies
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