A toll-like receptor agonist mimicking microbial signal to generate tumor-suppressive macrophages

Abstract

Switching macrophages from a pro-tumor type to an anti-tumor state is a promising strategy for cancer immunotherapy. Existing agents, many derived from bacterial components, have safety or specificity concerns. Here, we postulate that the structures of the bacterial signals can be mimicked by using non-toxic biomolecules of simple design. Based on bioactivity screening, we devise a glucomannan polysaccharide with acetyl modification at a degree of 1.8 (acGM-1.8), which specifically activates toll-like receptor 2 (TLR2) signaling and consequently induces macrophages into an anti-tumor phenotype. For acGM-1.8, the degree of acetyl modification, glucomannan pattern, and acetylation-induced assembly are three crucial factors for its bioactivity. In mice, intratumoral injection of acGM-1.8 suppresses the growth of two tumor models, and this polysaccharide demonstrates higher safety than four classical TLR agonists. In summary, we report the design of a new, safe, and specific TLR2 agonist that can generate macrophages with strong anti-tumor potential in mice.

Targeting Tumor Associated Macrophages to Overcome Conventional Treatment Resistance in Glioblastoma

“…Toll-like receptors (TLRs) are normally activated by microbial moieties (including nucleic acids) allowing macrophages to acquire a M1 phenotype. Using a TLR agonist to reprogram macrophages was thus of interest in cancer treatment (Feng et al, 2019). Numerous TLR7 ligands, TLR9 ligands, and one TLR8 ligand have been tested for their antitumoral properties in clinical trials ( Table 2).…”

The antitumoral activity of TLR7 ligands is corrupted by the microenvironment of pancreatic tumors

“…Among TLR family members, TLR2 activation of peripheral monocytes triggers differentiation into DC-SIGN+ macrophages, with robust M1 anti-tumoral phenotype 24 . Along the same line, recent work reports that acGM-1.8, a specific TLR-2 agonist, generates macrophages with strong anti-tumor potential in mice 8 . For TLR7, a recent report shows that R848, an agonist of TLR7 and TLR8, is a potent driver of the M1 phenotype in vitro and that R848-loaded nanoparticles target TAMs in vivo to impede colon tumor and melanoma growth in mice 25 .…”

“…On one hand, we found that CL347 treatment significantly decreases the number of lymphocytes infiltrating R211 tumors ( Fig. 5A and 5B); on the other hand, CL347 massively increases 8 the number of F4/80 positive cells in tumors ( Fig. 5A and 5C).…”

“…Recently, TLR2 agonists mimicking microbial signals were found to generate tumorsuppressive macrophages 8 . In another example, stimulating TLR7, an endosomal single strand (ss) RNA receptor associated with viral response and proinflammatory cytokines and type I interferon production 9 , inhibits programmed cell death protein 1 (PD-1) expression on T cells and promotes CD8-T-cell cytotoxic responses 10 .…”

Different activities of antitumor immunomodulators to induce neutrophil adherence response

“…Then, stimulated adherence by E. coli LPS, lipid A and OK-432 may be explained by the increased expression of CD11b/CD18 through TLR4 and the increased adherence by N-CWS and lipoteicoic acid may be mediated by TLR-2 expressed in neutrophils in addition to macrophages. As activation of TLR4 and TLR2 are reported to be tumoricidal (11,39), antitumor mechanism of bacterial BRMs may depend on the activation of TLR4 and/or TLR2 expressed in neutrophil in addition to macrophage. So far, the mechanism of antitumor effect of BRM was explained mainly through the activation of macrophage (40).…”