The role of gut microbiome in immune modulation in metastatic renal cell carcinoma

Abstract

Treatment of metastatic renal cell carcinomas (mRCC) has drastically improved since the advent of immunotherapy with immune checkpoint inhibitors (ICIs), with a significant proportion of patients achieving durable responses. While this has revolutionized treatment and improved outcomes for mRCC patients, a large subset of patients still does not respond to treatment with ICIs. Moreover, ICIs can induce various immune-related adverse events, limiting their use in many patients. Therefore, there is a need to identify the predictive biomarkers of both efficacy and toxicity associated with ICIs, which would allow for a more personalized approach and help with clinical decision-making. This review aims to explore the role of the gut microbiome in RCC to overcome primary resistance and predict response to treatment with ICIs. First, current therapeutic strategies and mechanisms of action of ICI therapies for RCC treatment will be reviewed. With the technological development of shotgun whole-genome sequencing, the gut microbiome has emerged as an exciting field of research within oncology. Thus, the role of the microbiome and its bidirectional interaction with ICIs and other drugs will be explored, with a particular focus on the microbiome profile in RCC. Lastly, the rationale for future clinical interventions to overcome resistance to ICIs using fecal microbiota transplantation in patients with RCC will be presented.

Keywords: immunotherapy; microbiome; predictive biomarker; renal cell carcinoma; tumor microenvironment.

Figure 1.

Mechanism of action of ICIs. CTLA-4 binds to B7, and PD-1 binds to PD-L1. Both of these interactions function to inhibit T-cell activation and immune response. Inhibiting the interaction between these receptors with ICIs allows the T cell to remain in an activated state, thus enhancing the host’s immune response. CD, cluster of differentiation; CTLA-4, cytotoxic T-lymphocyte-associated protein-4; ICIs, immune checkpoint inhibitors; MHC, major histocompatibility complex; PD-1, programmed cell death-1; PD-L1, programmed cell death ligand-1; TCR, T-cell receptor; +, activating interaction; −, inhibitory interaction.

Figure 2.

Modulation of the gut microbiome. The gut microbiome can be modulated by external environmental factors such as diet and drugs. This causes changes in the microbiota composition, and thus the downstream metabolites and cytokines. This leads to an impact on response to treatment with immunotherapy. Abx, antibiotics; CD, cluster of differentiation; FMT, fecal microbiota transplantation; IL, interleukin; MDSC, myeloid-derived suppressor cells; PPI, proton pump inhibitors; SCFA, short-chain fatty acids; sp., species; TME, tumor microenvironment; TNF, tumor necrosis factor.