Changes in the gut microbiome are known to affect the response to immunotherapy in patients with melanoma, but whether it is therefore possible that modulating gut dysbiosis could halt disease progression remains unclear. Clinical writer Rod Tucker investigates.
Cutaneous melanoma is the 17th most common cancer worldwide and the last 40 years has seen a steady increase in the number of cases, with a more than eight-fold increase from 1985 to 2018.
A further cause for concern is that melanoma has invasive metastatic growth patterns and is one of the most aggressive types of skin cancer.
Fortunately, in recent years, the introduction of immunotherapies has marked a major advancement in the treatment of melanoma. As a result, immunotherapy is now considered to be a promising new approach for the treatment of metastatic melanoma.
Curiously, one factor that appears to influence the outcome of immunotherapy in patients with melanoma is their gut microbiome.
This vast microbial community resides symbiotically within the human gut, contributing to homeostasis and regulating immune function. The terms microbiota and microbiome are often used interchangeably, although, strictly speaking, the ‘microbiome’ refers to a collection of genomes from all of the microorganisms, the microbial structural elements and metabolites.
The fact that the gut microbiome influences a patient’s response to chemotherapy, was first revealed in a 2013 study using mouse models. Researchers observed that among either antibiotic-treated or germ-free mice, tumour-infiltrating myeloid-derived cells responded poorly to chemotherapy.
Later work confirmed this relationship. Again, using mouse melanoma models, it was shown that supplementing with oral bifidobacterium, improved tumour control to the same degree as programmed cell death protein 1 ligand 1-specific antibody therapy.
This effect was also observed in humans in a 2017 study. Researchers examined the oral and gut microbiome of melanoma patients undergoing anti-programmed cell death 1 (anti-PD-1) immunotherapy. They were able to show via immune profiling, that there was an enhanced systemic and anti-tumour immunity in responding patients who had a favourable gut microbiome.
In fact, it became clear that there was a significant association between commensal microbial composition and clinical response in patients with metastatic melanoma.
Taken together, these findings made clear that a patient’s gut microbiome was able to influence their response to immune checkpoint inhibitor therapy. But the observations only raised more questions.
For example, was the diversity of the gut microbiome linked to the development of melanoma? Furthermore, did melanoma progress because of a gut dysbiosis? And, if the two were linked, could this information be used either prognostically or even therapeutically?
Gut microbiome and melanoma
Some answers to these emerging questions came from a recent study. Researchers were interested in exploring if there were any differences in the gut microbiome of patients with melanoma compared to healthy controls and between those at an early and late stage of the cancer.
The study, which was published in the journal JAMA Dermatology, characterised and compared gut microbiota profiles between healthy volunteers and patients with melanoma either at an early (stages 0 to II) or at a late stage (III to IV) of their disease.
A total of 228 participants were enrolled, of whom 49 were healthy controls, 38 had early stage disease and 141 had with late stage disease.
When comparing the microbiomes of individuals with melanoma against healthy controls, there were significant differences in alpha diversity with a higher number of unique species present among the healthy control group (p = 0.06).
But when looking at the beta diversity, which measures the differences between the two groups, healthy control samples formed distinct or distant communities as compared with patients who had melanoma (p <0.001). In fact, healthy controls had a greater abundance of the bacterial phyla Actinomycetota and Firmicutes.
One interesting observation was the higher level of species from the bacterial genus Fusobacterium, was significantly more abundant in the melanoma group compared to controls. This species has been found to be present at higher levels in patients with colorectal cancer and is associated with a shorter survival. Nevertheless, in the current study, while higher in melanoma patients, the difference was no longer significant after statistical adjustment.
When researchers compared the microbiome of those with early and late-stage melanoma, they found both a significantly higher alpha and beta diversity in those in the earliest stage of their cancer. In other words, it seems that melanoma progression is associated with a reduction in the diversity of the gut microbiome.
So, if microbiome diversity reduces as malignant melanoma progresses, could improving the alpha diversity prevent the subsequent development of the cancer?
Enhancing gut microorganisms
It is an intriguing thought that simply by enhancing the range of microorganisms within the gut, it could be possible to halt melanoma progression. And this idea may not be as far fetched as it might sound.
There is emerging evidence to suggest that improving the gut microbiome, might represent an effective adjunct to immunotherapy. For example, in a study from 2021, researchers showed that the use of faecal microbiota transplantation in 10 patients with anti-PD-1-refractory metastatic melanoma elicited a clinical responses in three patients: two achieved a partial response and one complete response.
More recently, in a second trial, researchers found that faecal microbiota transplantation from healthy donors to 20 patients with advanced melanoma who were in receipt of anti-PD-1 therapy, gave rise to an objective response rate of 65% and a complete response rate of 4%.
While faecal transplantation may not appeal to many, an alternative approach could be to increase alpha diversity with probiotics. In a case report of two patients with metastatic melanoma whose cancer progressed on immune checkpoint inhibitors, the combination of the Camu Camu probiotic with immunotherapy produced a both a complete and near complete response to therapy.
There is no doubt that the evidence to date has been able to shine a light on the importance of the gut microbiome in shaping a patient’s response to immunotherapy. Unfortunately, so far, research has only been able to demonstrates an association rather than causality. For instance, it remains unclear as to whether the reduced alpha diversity is actually the cause or merely a consequence, of melanoma progression. Research is also be hampered by the absence of what constitutes an ’optimal’ gut microbiome composition.
Despite these limitations, in the current era of precision medicine, a strategy that involves modulation therapy to improve the alpha diversity of the gut microbiome could play an important role in the future management of melanoma.
