Understanding the role of Toll-like receptors in lung cancer immunity and immunotherapy

Abstract

Lung cancer is currently the leading cause of cancer-related deaths worldwide. Significant improvements in lung cancer therapeutics have relied on a better understanding of lung cancer immunity and the development of novel immunotherapies, as best exemplified by the introduction of PD-1/PD-L1-based therapies. However, this improvement is limited to lung cancer patients who respond to anti-PD-1 immunotherapy. Further improvements in immunotherapy may benefit from a better understanding of innate immune response mechanisms in the lung. Toll-like receptors (TLRs) are a key component of the innate immune response and mediate the early recognition of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). TLR signaling modulates the tumor microenvironment from "cold" to "hot" leading to immune sensitization of tumor cells to treatments and improved patient prognosis. In addition, TLR signaling activates the adaptive immune response to improve the response to cancer immunotherapy through the regulation of anti-tumor T cell activity. This review will highlight recent progress in our understanding of the role of TLRs in lung cancer immunity and immunotherapy.

Keywords: Toll-like receptors; cancer immunity; immune checkpoint inhibitor; immunotherapy; innate immunity; lung cancer.

Figure 1

The roles of TLRs in lung cancer. Left panel: Human TLR1 to TLR9 recognize their ligands in pathogens (PAMPs) to activate MyD88-dependent (for all TLRs except TLR3) and TRIF-dependent (only for TLR3 and TLR4) pathways to induce innate immune responses in lung cancer. The activation of TLRs can show both pro- and anti-tumor activities depending on the setting. Right panel: Human TLR2 to TLR4 recognize endogenous ligands (DAMPs) in lung cancer, but these recognitions appear to induce only pro-cancer activity ( Table 1 ). This figure was generated using BioRender.