Toll-like receptor 4 activation in cancer progression and therapy

Abstract

Cancer immunotherapy has been the focus of intense research since the late 19th century when Coley observed that bacterial components can contribute to cancer regression by eliciting an antitumor immune response. Successful activation and maturation of tumor-specific immune cells is now known to be mediated by bacterial endotoxin, which activates Toll-like receptor 4 (TLR4). TLR4 is expressed on a variety of immune as well as tumor cells, but its activation can have opposing effects. While TLR4 activation can promote antitumor immunity, it can also result in increased tumor growth and immunosuppression. Nevertheless, TLR4 engagement by endotoxin as well as by endogenous ligands represents notable contribution to the outcome of different cancer treatments, such as radiation or chemotherapy. Further research of the role and mechanisms of TLR4 activation in cancer may provide novel antitumor vaccine adjuvants as well as TLR4 inhibitors that could prevent inflammation-induced carcinogenesis.

Figure 1

TLR4/MD-2 receptor complex recognizes and binds endotoxin. (a) MD-2 (shown in blue ribbons) is a soluble protein with a large hydrophobic pocket that directly binds bacterial endotoxin (red). One of the acyl chains of endotoxin (yellow) remains outside the hydrophobic pocket and mediates crucial interactions with TLR4 that bind the TLR4/MD-2 heterodimer together. Left: direct view of the MD-2 hydrophobic pocket. Right: side view showing the protruding endotoxin acyl chain. (b) The TLR4/MD-2/endotoxin heterodimer. Only the extracellular domains of TLR4 whose crystal structures were determined are shown [16].

Figure 2

TLR4 signaling in cancer—a struggle of antitumor immunity against cancer proliferation and immune evasion. TLR4 signaling on immune cells can enhance anti-tumor immunity by different mechanisms, including IL-12 or IFNγ upregulation and promotion of DC maturation and function (left side of the figure, depicted in green). On the other hand, TLR4 signaling on tumor cells can increase their tumorigenic potential (right side of the figure, depicted in red).