Role of Diet and Gut Microbiome on Clinical Outcomes in Patients with Advanced Melanoma

Vandoni, Giulia (2022). Role of Diet and Gut Microbiome on Clinical Outcomes in Patients with Advanced Melanoma. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.00014b53

Abstract

Background
In the past few years, the prognosis of patients with advanced melanoma has significantly improved thanks to the advent of targeted and immunotherapy. However, responses to therapies are currently limited approximately to 50% of the patients. The composition of gut microbiota (GM) has been correlated with a positive clinical response to several types of cancer therapies. However, little is known about how modifiable factors may influence the GM and how they can increase the therapeutic responses. To the best of my knowledge, no studies have jointly investigated diet, body composition, inflammatory parameters, immune profile, GM, and faecal metabolites in relation to the efficacy of cancer treatments. This represents the aim of the present research work.

Methods
I prospectively enrolled 31 patients with advanced cutaneous melanoma candidate to first-line immune or targeted therapy. I collected data regarding habitual diet to verify the adherence to a high-fibre Mediterranean diet (through Italian Mediterranean Index generated by EPIC questionnaire) and recent diet, to obtain current dietary fibre intake (using a 3-day food diary). Nutritional status was assessed by bioelectrical impedance analysis (BIA) and computed tomography (CT). Skeletal muscle index (SMI) was calculated from the analysis of CT images; the cut-offs used to identify sarcopenia are SMI < 38.5 cm²/m² for women and SMI < 52.4 cm²/m² for men. Systemic inflammation was evaluated by neutrophil-to-lymphocyte ratio (NLR) using available blood chemistry samples. The immune profile has been evaluated by the flow cytometer Gallios (Beckman Coulter). Faecal samples were stored to investigate 4 GM profile (16S rRNA gene sequencing was carried out using the Illumina Miseq platform), and faecal metabolites were analysed by gas chromatography-mass spectrometry (GC-MS).

Results
Responder patients were characterised by a BMI ≥ 30 kg/m², a non-sarcopenic status, a NLR < 4, and an increased proportion of Phascolarctobacterium in the GM. In contrast, non-responder patients were discriminated by an overabundance of Actinomyces, Clostridium, Dorea, Fusobacterium, Veillonella and by a high faecal level of butyric acid. No significant association was found between response rate and Italian Mediterranean Index or dietary fibre intake. The immune profile of non-responding patients, assessed only in the subset of patients undergoing immunotherapy, was characterized by higher median counts/μL of neutrophils, granulocytes and monocytic myeloid-derived suppressor cells (m-MDSCs).

Conclusion
This study confirms that complex patterns of association may exist between obesity, sarcopenia, inflammatory parameters, immune profile, GM, faecal metabolites, and response to treatment in advanced melanoma patients. Further studies are warranted to better investigate the causal relationship among all these factors, and possibly obtain biological insights able to impact the clinical practice.