A novel TLR7 agonist reverses NK cell anergy and cures RMA-S lymphoma-bearing mice

Abstract

Toll-like receptor 7 (TLR7) agonists are potent immune stimulants able to overcome cancer-associated immune suppression. Due to dose-limiting systemic toxicities, only the topically applied TLR7 agonist (imiquimod) has been approved for therapy of skin tumors. There is a need for TLR7-activating compounds with equivalent efficacy but less toxicity. SC1, a novel small molecule agonist for TLR7, is a potent type-1 interferon inducer, comparable to the reference TLR7 agonist resiquimod, yet with lower induction of proinflammatory cytokines. In vivo, SC1 activates NK cells in a TLR7-dependent manner. Mice bearing the NK cell-sensitive lymphoma RMA-S are cured by repeated s. c. administrations of SC1 as efficiently as by the administration of resiquimod. No relevant toxicities were observed. Mechanistically, SC1 reverses NK cell anergy and restores NK cell-mediated tumor cell killing in an IFN-α-dependent manner. TLR7 targeting by SC1-based compounds may form an attractive strategy to activate NK cell responses for cancer therapy.

A TLR7 agonist strengthens T and NK cell function during BRAF‐targeted therapy in a preclinical melanoma model

“…The peritumoral administration of imiquimod preserved the immunogenicity of the tumor and prolonged tumor control by maintaining high numbers of activated T and NK cells during BRAFi therapy. These findings fit to the observations that imiquimod has manifold effects on the activation of NK and T cells . We cannot exclude that other cell types might also be affected, since imiquimod as an immune response modifier has pleiotropic effects on different immune and nonimmune cell types …”

“…Furthermore, TLR7A has pleiotropic effects on T and NK cells and induces autophagic cell death in melanoma cells . Moreover, a recent study showed that a novel TLR7A reversed NK cell anergy and induced antitumor CD8 + T cell responses . Therefore, we assessed if treatment with a TLR7A as an immune modulator would be efficient in prolonging sensitivity to BRAFi.…”

“…Several studies indicate that TLR7 ligands can affect tumor growth and boost antitumor immunity. For example, the topical administration of imiquimod resulted in tumor control in the B16.F10 melanoma mouse model, whereas other studies characterized a novel TLR7 agonist that was able to revert the immunosuppressive tumor milieu by inducing effector T and NK cell responses . Moreover, local treatment with the TLR7 agonist imiquimod leads to the production of cytokines such as IFN‐α and IL‐12 by dendritic cells, which has subsequent positive effects on innate and adaptive immune cells .…”

“…We hypothesized that a TLR ligand‐mediated immune stimulation would be able to prevent this loss of immunogenicity. Recently, a study described that a novel TLR7 agonist reverted the suppressive tumor milieu leading to tumor cell killing by NK cells as well as T cells . Moreover, topical application of imiquimod (the only TLR7 agonist approved by FDA) is used for treatment of nonmelanoma skin cancer and provide beneficial effects in melanoma patients .…”

Natural killer cells in HIV-1 infection and therapy

“…Recent clinical study confirmed that MGN1703 treatment in HIV-1 infected patients on ART has a dual potential by increasing HIV-1 transcription and enhancing cytotoxic NK cell activation [179]. Other agonists able to boost NK cell effector functions against cancer cells are the ones binding TLR7 [180, 181]. These latter compounds have also been reported to increase both CD8+ T cell- and NK cell-mediated lysis of HIV-1-infected cells [172].…”