The Gastrointestinal Microbiome and Immune Checkpoint Inhibitors: A Review of Human Interventional Studies Among Melanoma Patients

February 2024 | Volume 23 | Issue 2 | 78 | Copyright © February 2024


Published online January 26, 2024

Nicole Natarelli BAa, Shaliz Aflatooni BSa, Aleena Boby BAa, Amanda Krenitsky MDb, James Grichnik MD PhDb,c

aUniversity of South Florida, Morsani College of Medicine, Tampa, FL
bUniversity of South Florida, Department of Dermatology and Cutaneous Surgery, Tampa, FL
cH. Lee Moffitt Cancer Center, Department of Cutaneous Oncology, Tampa, FL

Abstract
Immune checkpoint inhibitors (ICI) are widely utilized for the treatment of malignant melanoma. Interestingly, gastrointestinal microbiome composition has emerged as a predictive biomarker of immunotherapy outcomes. This review seeks to assess the effect of microbiota-modulatory interventions on the clinical and immunological response of metastatic melanoma treated with ICIs. A systematic search was performed to retrieve studies and cases involving any microbiota-modulating intervention. Three studies assessed the effect of fecal microbiota transplantation (FMT) on ICI efficacy, and one case report assessed its effect on clearance of ICI-associated colitis. Overall, 37.5% of melanoma patients who had been previously refractory to ICI immunotherapy demonstrated complete or partial response following FMT and subsequent immunotherapy. 65% of immunotherapy-naive melanoma patients demonstrated an objective response. No severe FMT-associated adverse events were reported, and FMT depicted efficacy in the remission of ICI-associated colitis. The results suggest that FMT may be a safe and moderately effective microbiota-modulating intervention to improve the efficacy of therapy in ICI-treated melanoma patients. Large, randomized, controlled trials are needed to determine optimal FMT donors and assess other microbiota-modulating interventions, such as pre- and probiotics, in melanoma patients. 

J Drugs Dermatol. 2024;23(2):78-84.     doi:10.36849/JDD.7674

INTRODUCTION

Melanoma and Immune Checkpoint Inhibitors 
Melanoma is a malignant neoplasm of the melanin-producing cells residing in the basal layer of the epidermis.1 Estimations depict 21.5 new cases of cutaneous melanoma diagnosed per 100,000 men and women in the United States annually.2 While there is a 99% five-year survival rate for localized cutaneous melanoma, distant metastasis dramatically decreases survival and calls for systemic therapeutic approaches.3 

Systemic immunotherapy, including immune checkpoint inhibitors (ICI), fosters long-term survival for some patients.4 Immune checkpoints suppress immune cell activity due to the binding of checkpoint proteins and partner proteins. For example, upon binding to programmed death protein 1 (PD-1) on T-cells, programmed death ligand 1 (PD-L1) suppresses cytotoxic T-cell activation. Similarly, binding of cytotoxic T-lymphocyte associated protein 4 (CTLA-4) with integral membrane protein B7 on antigen-presenting cells (APCs) downregulates T-cell activation by preventing the costimulatory interaction between B7 and CD28.5 Malignant melanocytes can express PD-L1 and CTLA-4.

The Microbiome 
The microbiome refers to the collection of microorganisms sharing a common habitat. The gastrointestinal microbiome represents the largest microbiome in the body and modulates gastrointestinal, metabolic, and dermatologic diseases. In addition, its role in the pathogenesis and treatment of metastatic melanoma has become better elucidated with novel research. The gut microbiota composition has been demonstrated to change as melanoma progresses from in situ, to invasive, and ultimately metastatic disease.7 Furthermore, microbiota composition has been shown to differ among melanoma patients and healthy counterparts.7 
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