The Use of TLR7 and TLR8 Ligands for the Enhancement of Cancer Immunotherapy

Abstract

After completing this course, the reader should be able to:1. Describe the subtypes of Toll-like receptor 7 and 8 agonists and their effect on the different components of the antitumor immune response.2. Argue why they are used as stand-alone immunotherapeutic agents.3. Evaluate their potential to improve current approaches of active and passive immunotherapy.This article is available for continuing medical education credit at CME.TheOncologist.com. CME CME ABSTRACT

The TLR7 agonists imiquimod and gardiquimod improve DC-based immunotherapy for melanoma in mice

“…Several synthetic compounds, such as imidazoquinoline molecules, and natural nucleoside structures have been characterized as TLR7 and/or TLR8 ligands. 13 After being recognized by TLR7 or TLR8, these ligands activate intracellular signaling pathways leading to the induction of type I IFNs, proinflammatory cytokines and chemokines. 5,13 The major benefit of TLR7/8 agonists is that they not only activate antigen-presenting cells, [14][15][16] but also promote activation of T and NK cells and inhibit regulatory T cell function.…”

“…13 After being recognized by TLR7 or TLR8, these ligands activate intracellular signaling pathways leading to the induction of type I IFNs, proinflammatory cytokines and chemokines. 5,13 The major benefit of TLR7/8 agonists is that they not only activate antigen-presenting cells, [14][15][16] but also promote activation of T and NK cells and inhibit regulatory T cell function. 13,[17][18][19][20] Moreover, TLR7/8 ligands have been shown to directly affect some tumor cells by inducing apoptosis and sensitizing tumor cells to killing mediated by CTLs and chemotherapeutic agents.…”

“…5,13 The major benefit of TLR7/8 agonists is that they not only activate antigen-presenting cells, [14][15][16] but also promote activation of T and NK cells and inhibit regulatory T cell function. 13,[17][18][19][20] Moreover, TLR7/8 ligands have been shown to directly affect some tumor cells by inducing apoptosis and sensitizing tumor cells to killing mediated by CTLs and chemotherapeutic agents. 21,22 However, these effects depend on the kinds of TLR7/8 agonists used and the type of tumor being treated.…”

“…25 In addition, topical TLR7 agonist treatment has not been shown to induce production of antibodies against self-antigens or development of systemic autoimmune diseases. 13 Systemic administration of TLR7 agonists requires higher dosages, which might result in some toxicity; specifically, higher doses of TLR7 agonists may result in influenza-like symptoms similar to those observed with IFN-a treatment. It is important to limit the dosage of TLR7 agonists in order to evoke local activation of the immune system without systemic cytokine induction.…”

“…11,12 Imiquimod has been approved by the US Food and Drug Administration for treating external genital and perianal warts and is also used for treatment of malignant tumors of the skin. 13 Imiquimod was recently shown to preferentially bind to TLR7 and, to a lesser extent, TLR8. Gardiquimod is a new imidazoquinoline compound developed and manufactured by InvivoGen (San Diego, CA, USA).…”