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Toll-like receptors and their role in carcinogenesis and anti-tumor treatment

Abstract

Toll-like receptors (TLRs) have been described as major components of the innate immune system, recognizing the conserved molecular structures found in the large groups of pathogens called pathogen-associated molecular patterns (PAMPs). TLR expression is ubiquitous, from epithelial to immunocompetent cells. TLR ligation triggers several adapter proteins and downstream kinases, leading to the induction of key pro-inflammatory mediators but also anti-inflammatory and anti-tumor cytokines. The result of this activation goes beyond innate immunity to shape the adaptive responses against pathogens and tumor cells, and maintains host homeostasis via cell debris utilization. TLRs have already become potent targets in infectious disease treatment and vaccine therapy and in neoplastic disease treatment, due to their ability to enhance antigen presentation. However, some studies show the dual effect of TLR stimulation on malignant cells: they can be proapoptotic or promote survival under different conditions. It is therefore crucial to design further studies assessing the biology of these receptors in normal and transformed cells. The established role of TLRs in human disease therapy is based on TLR7 and TLR4 agonists, respectively for the novel treatment of some types of skin cancer and for the anti-hepatitis B virus vaccine. Some clinical trials involving TLR agonists as potent enhancers of the anti-tumor response in solid tumors have begun.

Abbreviations

AJCC:

American Joint Committee on Cancer

AML:

acute myeloid leukemia

AP-1:

activator protein 1

APC:

antigen-presenting cell

CLL:

chronic lymphocytic leukemia

DC:

dendritic cell

FADD:

Fas-associated death domain

Flt3:

FMS-like tyrosine kinase 3

FL:

Flt3 ligand

HSP:

heat shock protein

IFN-γ:

interferon gamma

IL-1R:

Interleukin 1 receptor

IRF:

interferon regulatory factor

LBP:

LPS-binding protein

LPS:

lipopolysaccharide

MCP-1:

monocyte chemotactic protein 1

NF-κB:

nuclear factor kappa B

ODN:

oligodeoxynucleotide

PAMP:

pathogen-associated molecular pattern

SOCS1:

suppressor of cytokine signaling 1

TGF-β:

transforming growth factor beta

TIR:

Toll/Interleukin 1 receptor

TIRAP:

TIR domain-containing adapter protein or Mal

TLR:

Toll-like receptor

TNFα:

tumor necrosis factor alpha

TRAM:

TRIF-related adapter molecule

Treg:

regulatory T cells

TRIF:

TIR domain-containing adapter inducing IFNβ

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Wolska, A., Lech-Marańda, E. & Robak, T. Toll-like receptors and their role in carcinogenesis and anti-tumor treatment. Cell Mol Biol Lett 14, 248–272 (2009). https://doi.org/10.2478/s11658-008-0048-z

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Key words

  • Toll-like receptors
  • Innate immunity
  • Treatment
  • Carcinogenesis
  • Tumor
  • Vaccine
  • Dendritic cells