Microbiota triggers STING-type I IFN-dependent monocyte reprogramming of the tumor microenvironment

Au naturale: use of biologically derived cyclic di-nucleotides for cancer immunotherapy

“…Finally, an exciting study by Lam et al . [ 122 ] demonstrated that CDNs synthesized by the gut microbiota can enhance inflammation in the TME via Type I IFN signalling through STING activation. This anti-tumour response is primarily driven by increased populations of DCs, natural killer (NK) cells and anti-tumour macrophages.…”

“…Furthermore, faecal transplant of responders versus non-responders into mice showed a more inflamed TME and decreased tumour growth. This exciting study suggests that STING can be activated by natural CDNs in the gut by specifical microbial species, offering a new cornucopia of potential therapeutic innovations [ 122 ].…”

More fuel for the fire: Gut microbes and toxicity to immune agonist antibodies in cancer

“… 3 , 4 , 5 Mechanistic studies suggest that gut microbes play a key role in immune activation in the tumor microenvironment, including via c-di-AMP-mediated activation of the STING-IFN-I pathway (especially in NK cells), to promote robust anti-tumor immune responses ( Figure 1 ). 6 However, excessive immune activation with combined immune checkpoint blockade (CICB; anti-PD-1 and anti-CTLA-4) may drive immune-related adverse events (irAE), and gut microbes may contribute to this through stimulation of cytokines such as IL-1B and IL-6, with options to therapeutically target these. 7 However, gut microbes have been less well-studied in the context of treatment with IAAs.…”

“…Elegant mechanistic studies have now identified host targets through which gut microbes mediate anti-tumor immune responses to ICB via STING-mediated interferon signaling (gray arrow). 6 Additionally, Blake et al. show that gut microbes drive hepatotoxicity and cytokine release syndrome (CRS) to immune agonist antibodies (IAA) via MyD88 and other mechanisms in pre-clinical models (red arrow), with therapeutic targeting of gut microbes (via antibiotic treatment in this case) associated with reduced toxicity to therapy …”

Chemoproteomics of microbiota metabolites reveals small-molecule agonists for orphan receptor GPRC5A

“…1–3 For example, microbe-associated molecular patterns (MAMPs) such as lipopolysaccharides (LPS) can engage toll-like receptors (TLRs) to maintain intestinal epithelial homeostasis 4 and modulate infant autoimmunity 5 . In addition, microbiota-derived cyclic dinucleotides 6 and peptidoglycan fragments 7,8 initiate host immune response and enhance the efficacy of immune checkpoint inhibitor for cancer therapy 9,10 . Beyond generating MAMPs that engage canonical pattern recognition receptors (PRRs), microbiota metabolism of dietary components (e.g., polysaccharides, amino acids and lipids) 11 , host metabolites (e.g.…”