Association of Gut Microbiome with Immune Checkpoint Inhibitor Response in Advanced Melanoma

SUMMARY: The American Cancer Society estimates that in 2022, there will be an estimated 1.92 million new cancer cases diagnosed and 609,360 cancer deaths in the United States. Immunotherapy with Immune Checkpoint Inhibitors (ICIs) has revolutionized cancer care and has become one of the most effective treatment options by improving Overall Response Rate and prolongation of survival across multiple tumor types. These agents target Programmed cell Death protein-1 (PD-1), Programmed cell Death Ligand-1 (PD-L1), Cytotoxic T-Lymphocyte-Associated protein-4 (CTLA-4), and many other important regulators of the immune system. Over 50% of patients treated with a combination of PD-1 and CTLA-4 inhibitors are alive after five years. Nonetheless, less than 50% of the patients respond to single-agent ICI and a higher response to targeting both PD-1 and CTLA-4 is associated with significant immune-related Adverse Events.

Biomarkers predicting responses to ICIs include Tumor Mutational Burden (TMB), Mismatch Repair (MMR) status, and Programmed cell Death Ligand 1 (PD-L1) expression. Other biomarkers such as Tumor Infiltrating Lymphocytes (TILs), TIL- Interferon-gamma, Neutrophil-to-ratio, and peripheral cytokines, have also been proposed as predictors of response. It has been postulated that concomitant medications during therapy with ICIs such as baseline steroid use as well as treatment with antibiotics may negate or lessen the efficacy of ICIs.

Preclinical studies have suggested that immune-based therapies for cancer may have a very complex interplay with the host’s microbiome and there may be a relationship between gut bacteria and immune response to cancer. The gut microbiome is unique in each individual, including identical twins. The crosstalk between microbiota in the gut and the immune system allows for the tolerance of commensal bacteria (normal microflora) and oral food antigens and at the same time enables the immune system to recognize and attack opportunistic bacteria. Immune Checkpoint Inhibitors strongly rely on the influence of the host’s microbiome, and the gut microbial diversity enhances mucosal immunity, dendritic cell function, and antigen presentation. Broad-spectrum antibiotics can potentially alter the bacterial composition and diversity of our gut microbiota, by killing the good bacteria. It has been postulated that this may negate the benefits of immunotherapy and influence treatment outcomes. It should be noted however that the relationship between gut bacteria and immune response is influenced by several factors and may be partially cancer type specific and it is unlikely that the same microbiome features can reflect the uniqueness of the genetic and immune characteristics of each tumor.

Even though the composition of the gut microbiome has been associated with clinical responses to immune checkpoint inhibitor (ICI) treatment, there is a lack of consistency of results between the published studies, and there is limited consensus on the specific microbiome characteristics linked to the clinical benefits of ICIs. The Predicting Response to Immunotherapy for Melanona with Gut Microbiome and Metabolomics (PRIMM) studies are two separate prospective observational cohort studies that has been recruiting patients in the UK (PRIMM-UK) and the Netherlands (PRIMM-NL) since 2018. These cohorts of previously ICI-naive patients with advanced melanoma have provided extensive biosamples, including stool, serum and peripheral blood mononuclear cells, before and during ICI treatment, with detailed clinical and dietary data collected at regular intervals longitudinally.

The authors therefore performed a meta-analysis on existing publicly available datasets to produce the largest study to date. In order to study the role of the gut microbiome in ICI response, the researchers recruited ICI-naive patients with advanced cutaneous melanoma from the PRIMM cohorts, as well as three additional cohorts of ICI-naive patients with advanced cutaneous melanoma, originating from Barcelona, Leeds and Manchester (N = 165), and performed shotgun metagenomic sequencing on a total of 165 stool microbiome samples collected before initiating ICI treatment. Shotgun sequencing is a laboratory technique for determining the DNA sequence of an organism’s genome. This dataset was integrated with 147 metagenomic samples from smaller publicly available datasets. This methodology provided the largest assessment of the potential of the gut microbiome as a biomarker of response to ICI, in addition to allowing for investigation of specific microbial species or functions associated with response. Patient demographics including age, gender, BMI, previous non-immunotherapy treatments, previous drug therapies such as antibiotics, Proton Pump Inhibitors (PPIs) and steroids, as well as dietary patterns, were collected in these cohorts for the majority of patients, and were considered in the multivariate analysis.

The researchers used machine learning analysis to understand the association between gut microbiome and response to ICIs. This analysis confirmed the link between the microbiome and Overall Response Rates (ORRs), as well as Progression Free Survival (PFS) with ICIs. This analysis also revealed limited reproducibility of microbiome-based signatures across cohorts. A panel of species, including Bifidobacterium pseudocatenulatum, Roseburia spp. and Akkermansiamuciniphila were associated with responders, but no single species could be regarded as a fully reliable biomarker across studies. Based on these findings from this large set of real-world cohorts, the authors noted that the relationship between human gut microbiome and response to ICIs is more complex than previously understood, and extends beyond the presence or absence of different microbial species in responders and nonresponders.

It was concluded that future studies should include large samples and take into account the complex interplay of clinical factors with the gut microbiome over the treatment course. Until then, the authors recommend high-quality, diverse, whole-foods diet to optimize gut health, rather than consumption of commercial probiotics.

Cross-cohort gut microbiome associations with immune checkpoint inhibitor response in advanced melanoma. Lee KA, Thomas AM, Bolte LA, et al. Nat Med. 2022;28:535-544.