Optimizing therapeutic outcomes of immune checkpoint blockade by a microbial tryptophan metabolite

Abstract

BackgroundDespite the great success, the therapeutic benefits of immune checkpoint inhibitors (ICIs) in cancer immunotherapy are limited by either various resistance mechanisms or ICI-associated toxic effects including gastrointestinal toxicity. Thus, novel therapeutic strategies that provide manageable side effects to existing ICIs would enhance and expand their therapeutic efficacy and application. Due to its proven role in cancer development and immune regulation, gut microbiome has gained increasing expectation as a potential armamentarium to optimize immunotherapy with ICI. However, much has to be learned to fully harness gut microbiome for clinical applicability. Here we have assessed whether microbial metabolites working at the interface between microbes and the host immune system may optimize ICI therapy.MethodsTo this purpose, we have tested indole-3-carboxaldehyde (3-IAld), a microbial tryptophan catabolite known to contribute to epithelial barrier function and immune homeostasis in the gut via the aryl hydrocarbon receptor (AhR), in different murine models of ICI-induced colitis. Epithelial barrier integrity, inflammation and changes in gut microbiome composition and function were analyzed. AhR, indoleamine 2,3-dioxygenase 1, interleukin (IL)-10 and IL-22 knockout mice were used to investigate the mechanism of 3-IAld activity. The function of the microbiome changes induced by 3-IAld was evaluated on fecal microbiome transplantation (FMT). Finally, murine tumor models were used to assess the effect of 3-IAld treatment on the antitumor activity of ICI.ResultsOn administration to mice with ICI-induced colitis, 3-IAld protected mice from intestinal damage via a dual action on both the host and the microbes. Indeed, paralleling the activation of the host AhR/IL-22-dependent pathway, 3-IAld also affected the composition and function of the microbiota such that FMT from 3-IAld-treated mice protected against ICI-induced colitis with the contribution of butyrate-producing bacteria. Importantly, while preventing intestinal damage, 3-IAld did not impair the antitumor activity of ICI.ConclusionsThis study provides a proof-of-concept demonstration that moving past bacterial phylogeny and focusing on bacterial metabolome may lead to a new class of discrete molecules, and that working at the interface between microbes and the host immune system may optimize ICI therapy.

Microbial Metabolites as Ligands to Xenobiotic Receptors: Chemical Mimicry as Potential Drugs of the Future

“…This raises the possibility that different activators/inducers may augment receptor bias regarding which phenotypes might be most affected. In this context, in a mouse model of immune cancer checkpoint (ICI) induced colitis, indole 3-carboxaldehyde alleviated colitis without affecting the anti-tumor efficacy of the ICI (Renga, Nunzi et al 2022). Enteric formulated indole 3-carboxaldehyde has been characterized for therapeutic use in murine metabolic syndrome (Puccetti, Pariano et al 2021).…”

Effect of Gut Microbiota-Derived Metabolites on Immune Checkpoint Inhibitor Therapy: Enemy or Friend?

“…Indole-3-carboxaldehyde (3-IAld) could attenuate colitis induced by ICIs in mice, but did not affect therapeutic efficacy. The beneficial activity of 3-IAld was achieved by increasing the intestinal barrier through the AhR/Il-22 axis and controlling inflammation through Treg cells [ 46 ] ( Figure 4 , Table 1 ).…”

Pharmaceutically Active Microbial AhR Agonists as Innovative Biodrugs in Inflammation

“…Along the same reasoning, enteric formulated 3-IAld was able to activate AhR locally and to prevent immunopathologies, intestinal epithelial barrier dysfunction and liver complications in preclinical models of metabolic inflammation and liver injury [ 48 , 64 ]. Finally, 3-IAld formulated for localized delivery in the gut protected mice from intestinal damage via dual action on both the host and the microbe sides in checkpoint-inhibitor-induced gastrointestinal toxicity [ 65 ]. It is worth noting here that protection by 3-IAld occurred via dual action on both the host and the microbes sites.…”

“…It is worth noting here that protection by 3-IAld occurred via dual action on both the host and the microbes sites. Indeed, paralleling the activation of the host AhR/IL-22-dependent pathway, 3-IAld also affected the composition and function of the microbiota such that fecal microbiome transplantation from 3-IAld-treated mice protected against gut inflammation [ 65 ].…”