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A Nature Medicine study published earlier this year entitled “Cross-cohort gut microbiome associations with immune checkpoint inhibitor response in advanced melanoma” outlines the critical roles of the gut microbiome in mediating the benefits of cancer immunotherapies in the treatment of melanoma [1]. At a high level, this paper is an important reminder of just how instrumental the gut microbiome is to aspects of health that appear unrelated to the gut at first blush.
Indeed, the microbes that live in the gut not only affect gastrointestinal health, but they also secrete molecules that enter the circulation and modulate host metabolism, gene expression, immune system regulation and more across the tissues of the body. In addition to the extensive interplay between the microbiome and the host, the microbiome can also influence the efficacy of drug molecules consumed by the host. One such class of drugs whose effectiveness has been shown to be, at least partially, dependent upon gut microbiome composition are the cancer immunotherapeutics known as immune checkpoint inhibitors (ICIs) [1].
The goal of immunotherapies in general is to stimulate the immune system to help it to recognize and eliminate cancer cells. ICIs are monoclonal antibodies designed to bind to specific receptors on immune cells. They have shown particular promise in the treatment of several malignancies including melanomas. However, although ICIs have improved outcomes for many patients, the indiscriminate activation of the immune system can also come with a range of side effects that often manifests as autoimmune reactions [2].
In the context of melanoma, the combined use of two particular ICIs (PD-1 and CTLA-4 antibodies) has become standard of care. However, the heterogenous response to these treatments has motivated researchers to study the factors affecting both their efficacy and side effects. Specifically, the gut microbiome has emerged as not only a biomarker of whether the treatments will be effective in an individual, but also as a therapeutic target.
Recent studies have associated higher relative abundances of Akkermansia muciniphila, Alistipes, Firmicutes, Faecalibacterium prausnitzii, Bifidobacterium longum, and Bacteroides caccae in individuals responsive to the standard-of-care treatment. However, not all of the studies achieved the same microbiome signatures in responders, likely due to differences in sample collection and preparation, as well as dietary and medication variability across cohorts.
To determine whether specific features of the gut microbiome directly influence patient responses to ICI treatment
In an attempt to normalize for the factors that contributed to the microbiome variability across previous cohorts, the authors used samples collected from the Predicting Response to Immunotherapy for Melanoma with Gut Microbiome and Metabolomics (PRIMM) study, which consists of large cohorts of ICI-naive patients with advanced cutaneous melanoma (stage III and stage IV) who provided extensive biological samples as part of the assessment. These samples included stool, serum, and peripheral blood mononuclear cells before and during treatment with ICIs, as well as detailed information about clinical interactions and dietary intake. In total, 165 stool samples were analyzed alongside 147 samples from smaller public datasets. This effort represents the largest and most comprehensive assessment of the interactions between the gut microbiome and ICI responsiveness to date.
There were no differences in alpha diversity (i.e. the measure of the number of different bacterial species present in one sample) across all cohorts that broadly explained the differential responses of patients to ICI treatment. However, within cohorts, associations between microbiome composition and treatment response were observed. The absence of cross-cohort microbial signatures for ICI response indicates that subtle features, and not global shifts, of the microbiome are likely responsible for differential treatment response.
Specifically, two uncultivated species of Rosburia (CAG:182 and CAG:471) were consistently overrepresented among ICI responders. In a recent large population-based study, Rosburia sp. CAG:18 was one of five species most highly associated with metabolic and cardiovascular health, and was inversely correlated with inflammatory status. To learn more about Rosburia sp. CAG:18, see our previous article.
Across all datasets, Phascolarctobacterium succinatutens and Lactobacillus vaginalisalso emerged as significantly enriched among responders, and Akkermansia muciniphila and Dorea formicigeneransprevalence corresponded with progression-free survival after 12 months of treatment and overall response rates. Additionally, the bacterium Eubacterium rectale was associated with both response to ICI treatment and lower levels of ICI toxicity in patients.
In general, most of the bacteria overrepresented among ICI responders are those that have been shown to have a strong association with overall health within the microbiome literature at large. These include
whose levels exhibit a positive correlation with successful immunotherapy cancer treatment as reported by previous studies.
Conversely, Bacteroides clarus was overrepresented among ICI nonresponders across all datasets, indicating that this bacterium may directly or indirectly contribute to poor outcomes in melanoma patients treated with ICIs. In fact, not only was Bacteroides clarus associated with failure to respond to ICI treatment, but it was also associated with enhanced ICI toxicity. Another biomarker of nonresponders that emerged was the bacterium Ruminococcus gnavus—a member of the microbiome whose levels correspond to several diseases and poor cardiovascular and metabolic health.
The influence of the microbiome on ICI treatment efficacy is complex and likely dependent upon the interactions between specific species in the gut. Moreover, given the highly unique nature of each individual’s microbial ecosystem, the ability to select for the most effective and least toxic treatments will require technological advances in deep sequencing of the microbiome to more rigorously tease out the bacterial composition. However, there are several members of the microbiome that are associated with enhanced ICI response and diminished toxicity, most of which are broadly associated with health in general. Therefore, general optimization of the gut microbiome through the consumption of prebiotics, specific combinations of prebiotics and probiotics, and fermented foods may will not only benefit digestive and immune health, but may also improve an individual’s response to pharmaceutical treatments like ICIs.
Author:
Dr. Alexis Cowan, a Princeton-trained PhD specializing in the metabolic physiology of nutritional and exercise interventions.
Follow Dr. Cowan on Instagram: @dralexisjazmyn
[1] Lee KA, Thomas AM, Bolte LA, Björk JR, de Ruijter LK, Armanini F, Asnicar F, Blanco-Miguez A, Board R, Calbet-Llopart N, Derosa L, Dhomen N, Brooks K, Harland M, Harries M, Leeming ER, Lorigan P, Manghi P, Marais R, Newton-Bishop J, Nezi L, Pinto F, Potrony M, Puig S, Serra-Bellver P, Shaw HM, Tamburini S, Valpione S, Vijay A, Waldron L, Zitvogel L, Zolfo M, de Vries EGE, Nathan P, Fehrmann RSN, Bataille V, Hospers GAP, Spector TD, Weersma RK, Segata N. Cross-cohort gut microbiome associations with immune checkpoint inhibitor response in advanced melanoma. Nat Med. 2022 Mar;28(3):535-544. doi: 10.1038/s41591-022-01695-5. Epub 2022 Feb 28. PMID: 35228751; PMCID: PMC8938272.
[2] Franzin R, Netti GS, Spadaccino F, Porta C, Gesualdo L, Stallone G, Castellano G, Ranieri E. The Use of Immune Checkpoint Inhibitors in Oncology and the Occurrence of AKI: Where Do We Stand? Front Immunol. 2020 Oct 8;11:574271. doi: 10.3389/fimmu.2020.574271. PMID: 33162990; PMCID: PMC7580288.
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