A novel gut-restricted small molecule TLR2 agonist enhances immune checkpoint inhibitor efficacy in a preclinical mouse fibrosarcoma tumor model
نویسندگان
چکیده
Immune checkpoint inhibitor (ICI) therapy has revolutionized cancer treatment, but patient response remains variable. Substantial research been focused on understanding the tumor-intrinsic and tumor-extrinsic factors underlying response. Recently, gut microbiome emerged as a modulator of ICI in both human patients mouse tumor models. Antibiotic treatment deleterious effects efficacy retrospective studies have identified signatures associated with responders non-responders. Furthermore, fecal matter transplant (FMT) from can improve non-responders, however there is substantial variability that may be attributable to imprecise nature FMT. We Toll-like Receptor 2 (TLR2) key receptor mediating microbial impact host immunity are developing novel gut-restricted small molecules specifically engage activate gut-resident TLR2. Compound A showed pro-inflammatory activity vitro, eliciting broad cytokine macrophage-like cell lines low nanomolar potency. significantly restored anti-PD1 vivo model where antibiotics abrogated efficacy. In this model, mice bearing MCA205 fibrosarcoma tumors responded well delayed growth prolonged survival. attenuated therapy, presence antibiotics. conclude related analogs potential enhance by modulating anti-tumor immune via activation TLR2 gut. Further mechanistic pharmacological additional models progress. Conflict interest: Ownership: JS, CJO, RKS, MC, RG, ASC employees shareholders Axial Therapeutics. PS shareholder
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ژورنال
عنوان ژورنال: European Journal of Cancer
سال: 2022
ISSN: ['0959-8049', '1879-0852']
DOI: https://doi.org/10.1016/s0959-8049(22)01139-x