Molecular pathways: toll-like receptors in the tumor microenvironment--poor prognosis or new therapeutic opportunity

Abstract

Numerous reports have described Toll-like receptor (TLR) expression in the tumor microenvironment as it relates to cancer progression, as well as their involvement in inflammation. While TLRs mediate immune surveillance, clinical studies have associated TLR expression in the tumor with poor patient survival, indicating that TLR expression may affect cancer treatment and survival. This review will examine mechanisms in which TLR activation upregulates protumorigenic pathways, including the induction of inducible nitric oxide synthase (iNOS2) and COX2, which in turn increase TLR expression and promote a feed-forward loop leading to tumor progression and the development of more aggressive tumor phenotypes. These propagating loops involve cancer cell, stroma, and/or immune cell TLR expression. Because of abundant TLR expression in many human tumors, several TLR agonists are now in clinical and preclinical trials and some have shown enhanced efficacy when used as adjuvant with radiation, chemotherapy, or cancer vaccines. These findings suggest that TLR expression influences cancer biology and therapeutic response, which may involve specific interactions within the tumor microenvironment, including mediators of inflammation such as nitric oxide and the arachidonic acid signaling pathways.

Figure 1.

Influence of TLR signaling on patient with cancer therapeutic outcome tumor cells in a chronically inflamed tumor microenvironment usurp host immunity through tumor cell and immune cell TLR activation leading to increased NOS2/COX2 and the recruitment of immunosuppressive cell types that reduce host tumor surveillance and diminish therapeutic response. Alternatively, the activation of TLRs expressed on CD8+ T cells mediates an M1 antitumor response.