In a recent study published in the Cell journal, researchers showed how a dietary tryptophan (Trp) metabolite synthesized by the probiotic Lactobacillus reuteri (Lr) invaded the gut-distal tumor microenvironment (TME) of melanoma patients and facilitated their immune checkpoint inhibitor (ICI) treatment.
Study: Dietary tryptophan metabolite released by intratumoral Lactobacillus reuteri facilitates immune checkpoint inhibitor treatment. Image Credit: Kateryna Kon/Shutterstock.com
In this way, they evidenced the role of aryl hydrocarbon receptor (AhR) antagonist indole-3-aldehyde (I3A) in promoting ICI effectiveness and survival in severe melanoma cases.
The probiotic Lr translocated to, colonized, and persisted within melanoma and released I3A, a microbial AhR ligand, to promote Lr- and ICI-triggered interferon-gamma (IFN-γ)-producing cluster of differentiation 8 (CD8)+ T cells locally, drive antitumor immunity, thereby bolstering ICI.
There is a knowledge gap regarding the mechanisms driving ICI responsiveness in cancer patients via probiotics. Also, studies have not yet deciphered whether translocated bacteria impact tumor immunity or ICI from directly within the tumor.
In other words, researchers have not yet explored this critical microbial-host crosstalk despite the recent identification of gut-distal tumor microbiomes and studies showing their impact on tumor immunity and response to ICI.
In a recent study, researchers found that microbial AhR ligands exhibited pro-tumorigenic effects in a mouse pancreatic cancer model by activating the AhR in myeloid cells.
However, clinical trials aimed at blocking endogenous AhR signaling using indoleamine-2,3-dioxygenase (IDO)* blockers failed to prevent melanoma progression, thereby highlighting the importance of studying the role of microbial-metabolite-mediated AhR activation in preclinical cancer models.
*(Note that IDO is a cellular enzyme that depletes cells of tryptophan to exert an immunosuppressive effect, thereby helping tumors escape the immune system).
About the study
In the present study, researchers used a preclinical cancer model to test the antitumorogenicity of four probiotic bacteria, Lactobacillus johnsonii (Lj), Lactobacillus reuteri (Lr), Bifidobacterium longum (Bl), and Escherichia coli (E. coli).
To this end, they treated specific-pathogen-free (SPF) mice with select bacterial taxa using oral gavage (OG) every day and investigated which tumor-suppressing strain increased ICI efficacy the most.
Further, they examined the clinical relevance of their findings in a group of advanced melanoma patients.
The researchers found that Lr generated the most robust antitumor immunity by releasing AhR agonist and dietary Trp catabolite, I3A.
I3A exerted its effects through CD8+ T cell-specific AhR signaling, which promoted IFN-γ-production and enhanced ICI. Strikingly, though a Trp-enriched diet was adequate to facilitate ICI, it needed AhR activity within CD8+ T cells.
Overall, the researchers uncovered a critical microbial-host crosstalk within the TME of melanoma patients that drove spontaneous antitumor immunity and facilitated ICI in preclinical melanoma.
It is well-recognized that Lactobacillus sp. and E. coli are abundant in the feces of ICI-responding melanoma patients.
Together, these observations should prompt other researchers to address this mechanism in other AhR ligand-releasing bacteria in future studies, given this mechanism might be a unifying antitumor mechanism conserved across numerous ICI-response-related microbial taxa.
The study findings also pointed out that Lr-derived I3A-triggered antitumor immunity was restricted to the tumor microenvironment (TME), highlighting the role of the local environment in mounting a response to tumor-invading CD8+ T cells to I3A.
The present study showed that a probiotic bacterium (Lr) translocated to gut-distal melanoma TME remained viable within the tumor and promoted antitumor immunity.
It remarkably highlighted and elucidated that probiotics could help enhance the antitumor immunity of cancer patients, especially those undergoing ICI treatment.
Since this work and other previous works have established that AhR activation in cancer progression is ligand-specific, future studies should aim at distinguishing the exogenous vs. endogenous AhR activation within CD8+ T cells and their influence on tumor immunity.
However, provided ICIs might trigger autoimmune responses in some cases, a higher Lr intake might trigger such autoimmune events in genetically predisposed individuals. Future clinical studies should consider this important confounding factor in preclinical investigations.
Nevertheless, this study has translational potential for several reasons. First, Lr is naturally abundant in the human gut and widely used in probiotics. The Lr strain used in this study was a human-isolated Lr strain that secreted I3A.
Other studies should examine the role of I3A in patients with ICI-resistant cancers. Its establishment as a biomarker for ICI sensitivity could help find new dietary and probiotic combination treatment strategies for melanoma patients regardless of their ICI response.