Microbiomes modulate the local immune response, influencing immunotherapy response and toxicity

Immunotherapy has revolutionized the treatment of several cancers. However, it remains elusive why only some patients benefit from these treatments and why some patients experience immune-related adverse events (irAEs). Microbiomes are under investigation to understand their implication in the heterogenous response to immunotherapies. Indeed, through their immune-modulating proprieties, microbiomes can modulate the local immune response, influencing immunotherapy response and toxicity.

Gut and tumor microbiomes can be linked to immunotherapy response in cancer patients

Immune checkpoint inhibitors (ICI) targeting programmed cell death protein (PD-1)/programmed cell death ligand (PD-L1) and cytotoxic T lymphocyte-associated protein (CTLA-4) axis have led to a paradigm shift in the treatment of several cancers. Unfortunately, only a minority of patients experienced a positive and durable response to ICI. Currently, biomarkers to explain and predict this response heterogeneity are lacking.

Recent studies have shown that antibiotic use can reduce the effectiveness of ICI. Responders to ICI can also be differentiated from non-responders based on their gut microbiota composition. The administration of certain bacterial strains has even been shown to confer sensitivity to ICI.

For more information on this topic, read our previous synopsis:”Resistance to anti-PD-1 immunotherapy can be attributed to the gut microbiome”

Microbiomes, by modulating the immune response, are also involved in ICI toxicity

The heterogeneity of patient responses to ICI is not limited to treatment efficacy but also extends to toxicity. Indeed, some patients experience treatment-limiting toxicities, referred to as immune-related adverse events (irAEs). These irAEs are commonly from dermatological, gastrointestinal, pulmonary, hepatic, and endocrine origin; and less frequently from ocular, metabolism (type 1 diabetes), cardiac, neurological, and hematological origin. The management of cancer patients is complicated by these irAEs and can lead to treatment discontinuation, thus affecting the immunotherapy outcome.

Several studies point out the role of microbiomes in irAEs. Factors such as antibiotic use, aging and obesity, can impact the microbiome leading to dysbiosis and contributing to irAEs. The association between gut microbiota and irAEs has mainly been studied in the context of immune-mediated colitis and anti-CTLA-4 treatment. In murine models, anti-CTLA-4 mAB has been shown to induce a “subclinical colitis” dependent on the gut microbiota, as this colitis was less prominent in germ-free mice. This anti-CTLA-4-induced colitis was improved by oral administration of Bacteroides fragilis and Burkholderia cepacia. B. fragilis may promote the proliferation of ICOS+ Tregs that secrete IL-10 (an anti-inflammatory cytokine) in the lamina propria, and so having a protective effect on ICI-induced colitis. The gut microbiota may also have an anti-inflammatory effect by stimulating the Treg cell differentiation.

Microbiome mediation of irAEs is not limited to colitis. Recent evidence from murine models suggests that microbiota is a key internal factor driving lethal myocarditis. Peptides derived from Bacteroides thetaiotaomicron and Bacteroides faecis β-galactosidase are similar to myosin heavy chain 6, thereby highlighting the potential pathological role of cross-reactive T-cells that proliferate in the gut lamina propria and eventually lead to myocarditis.

Targeting the microbiomes to improve immunotherapy efficacy and toxicity

A better understanding of the mechanisms underpinning the interplay between ICI-induced anti-tumor immunity and the immune-modulatory role of the gut, tumor, and local microbiomes may open new ways to improve outcomes of cancer immunotherapies.

In murine models, a cocktail of Bacteroidales and Burkholderiales was seen to ameliorate CTLA-4-blockade-induced subclinical colitis and colon inflammatory scores in antibiotic-treated mice. In another study, oral administration of four Bifidobacterium species ameliorated ICI-induced colitis. Modulation of the gut microbiota using antibiotics was also shown to prevent lethal cardiomyopathy and reduce cardiac inflammation. Several cases of ICI-associated refractory colitis successfully treated with FMT (fecal microbial transplantation) were also reported, providing preliminary evidence to support the modulation of the gut microbiome to treat ICI-related colitis

The potential role of the human gut microbiome in modulating response to ICI has generated considerable interest in the development of microbiome-based therapies. A number of early-phase clinical trials are underway exploring the ability of microbial therapies to augment the efficacy and decrease the toxicity of immunotherapies.

In their review, Naqash and colleagues (2021) highlight the importance of microbiomes in immunotherapies not only on their efficacy but also on their toxicity. Microbiomes are a new source of biomarkers to predict successful and adverse immunotherapy outcomes. Their modulation also presents a new source of additional therapies to improve the efficacy and adherence to ICI treatments.

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The role of gut microbiome in modulating response to immune checkpoint inhibitor therapy in cancer

Naqash AR, Kihn-Alarcón AJ, Stavraka C, Kerrigan K, Maleki Vareki S, Pinato DJ, Puri S. Ann Transl Med. 2021 Jun;9(12):1034. doi: 10.21037/atm-20-6427. PMID: 34277834; PMCID: PMC8267312.

Abstract :

Immunotherapy has led to a paradigm shift in the treatment of several cancers. There have been significant efforts to identify biomarkers that can predict response and toxicities related to immune checkpoint inhibitor (ICPI) therapy. Despite these advances, it has been challenging to tease out why a subset of patients benefit more than others or why certain patients experience immune-related adverse events (irAEs). Although the immune-modulating properties of the human gut bacterial ecosystem are yet to be fully elucidated, there has been growing interest in evaluating the role of the gut microbiome in shaping the therapeutic response to cancer immunotherapy. Considerable research efforts are currently directed to utilizing metagenomic and metabolic profiling of stool microbiota in patients on ICPI-based therapies. Dysbiosis or loss of microbial diversity has been associated with a poor treatment response to ICPIs and worse survival outcomes in cancer patients. Emerging data have shown that certain bacterial strains, such as Faecalibacterium that confer sensitivity to ICPI, also have a higher propensity to increase the risk of irAEs. Additionally, the microbiome can modulate the local immune response at the intestinal interface and influence the trafficking of bacterial peptide primed T-cells distally, influencing the toxicity patterns to ICPI. Antibiotic or diet induced alterations in composition of the microbiome can also indirectly alter the production of certain bacterial metabolites such as deoxycholate and short chain fatty acids that can influence the anti-tumor tolerogenesis. Gaining sufficient understanding of the exact mechanisms underpinning the interplay between ICPI induced anti-tumor immunity and the immune modulatory role gut microbiome can be vital in identifying potential avenues of improving outcomes to cancer immunotherapy. In the current review, we have summarized and highlighted the key emerging data supporting the role of gut microbiome in regulating response to ICPIs in cancer.

Keywords : Gut microbiome, response, toxicity, immunotherapy

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