Microbial Influences on Immune Checkpoint Inhibitor Response in Melanoma: The Interplay between Skin and Gut Microbiota

Abstract

Immunotherapy has revolutionized the treatment of melanoma, but its limitations due to resistance and variable patient responses have become apparent. The microbiota, which refers to the complex ecosystem of microorganisms that inhabit the human body, has emerged as a promising area of research for its potential role in melanoma development and treatment response. Recent studies have highlighted the role of microbiota in influencing the immune system and its response to melanoma, as well as its influence on the development of immune-related adverse events associated with immunotherapy. In this article, we discuss the complex multifactorial mechanisms through which skin and gut microbiota can affect the development of melanoma including microbial metabolites, intra-tumor microbes, UV light, and the immune system. In addition, we will discuss the pre-clinical and clinical studies that have demonstrated the influence of different microbial profiles on response to immunotherapy. Additionally, we will explore the role of microbiota in the development of immune-mediated adverse events.

Keywords: gut microbiota; immune checkpoint inhibitors; immune-related adverse events; melanoma; skin microbiota.

Figure 1

Mode of action of immune checkpoint inhibitors [8]. Immune checkpoint inhibitors work by targeting specific mechanisms that prevent T cells from attacking cancer cells in the body. One such mechanism involves the binding of B7-1/B7-2 to CTLA-4, which keeps T cells inactive and unable to kill cancer cells. Anti-CTLA-4 antibodies block this binding, enabling the T cells to become active and attack cancer cells. Another mechanism involves the binding of PD-L1 to PD-1, which also prevents T cells from attacking cancer cells. Anti-PD-1/PD-L1 antibodies interrupt this binding and enhance the ability of T cells to target and kill cancer cells.

Figure 2

Proposed mechanisms of microbial influence on the response to immune checkpoint-inhibitors. These include production of inosine, anabolic amino acids, short chain fatty acids, as well as molecular mimicry between microbial and self-antigen. Through these mechanisms, microbiota can affect the immune cell infiltration into the tumor cells and consequent responses to immune-checkpoint inhibitors.