Implication of the Gut Microbiome and Microbial-Derived Metabolites in Immune-Related Adverse Events: Emergence of Novel Biomarkers for Cancer Immunotherapy

Abstract

Immune checkpoint inhibitors (ICIs) have changed how we think about tumor management. Combinations of anti-programmed death ligand-1 (PD-L1) immunotherapy have become the standard of care in many advanced-stage cancers, including as a first-line therapy. Aside from improved anti-tumor immunity, the mechanism of action of immune checkpoint inhibitors (ICIs) exposes a new toxicity profile known as immune-related adverse effects (irAEs). This novel toxicity can damage any organ, but the skin, digestive and endocrine systems are the most frequently afflicted. Most ICI-attributed toxicity symptoms are mild, but some are severe and necessitate multidisciplinary side effect management. Obtaining knowledge on the various forms of immune-related toxicities and swiftly changing treatment techniques to lower the probability of experiencing severe irAEs has become a priority in oncological care. In recent years, there has been a growing understanding of an intriguing link between the gut microbiome and ICI outcomes. Multiple studies have demonstrated a connection between microbial metagenomic and metatranscriptomic patterns and ICI efficacy in malignant melanoma, lung and colorectal cancer. The immunomodulatory effect of the gut microbiome can have a real effect on the biological background of irAEs as well. Furthermore, specific microbial signatures and metabolites might be associated with the onset and severity of toxicity symptoms. By identifying these biological factors, novel biomarkers can be used in clinical practice to predict and manage potential irAEs. This comprehensive review aims to summarize the clinical aspects and biological background of ICI-related irAEs and their potential association with the gut microbiome and metabolome. We aim to explore the current state of knowledge on the most important and reliable irAE-related biomarkers of microbial origin and discuss the intriguing connection between ICI efficacy and toxicity.

Immune‐related adverse events in non‐small cell lung cancer: Occurrence, mechanisms and therapeutic strategies

“…As previously mentioned, the role of the gut microbiome is vital in maintaining homeostasis in the host's gut and other sites, significantly influencing the development of irAEs 145,154 . Consequently, the role of specific gut microbiomes is gaining increasing recognition 139,143,149 . Future research should focus on identifying specific microbiomes that can optimise the outcomes of cancer immunotherapy.…”

“…Short‐chain fatty acids (SCFAs), including propionate, butyrate, acetate and valeric acid, are essential in engaging with immune cells, particularly colonic macrophages, and suppressing the synthesis of proinflammatory cytokines such as IL‐1, TNF‐α and IL‐6 144–146 . Similar to SCFAs, compounds such as indole‐3‐carboxaldehyde and polyamines, including spermine, are expected to offer defense against the development of irAEs 143,147 . Particularly, a study of the stool microbiota in 26 patients showed that most baseline phylotypes in those with colitis belonged to the Firmicutes group, whereas individuals without colitis fell under the Bacteroidetes category 148 .…”

“…Emerging evidence suggests that specific gut microbiota members, such as Faecalibacterium, Bacteroides and Clostridium, contribute to maintaining immune balance in the host. This balancing act is achieved through the promotion of Treg growth and cytokine production, factors implicated in the onset of irAEs 143 . Short‐chain fatty acids (SCFAs), including propionate, butyrate, acetate and valeric acid, are essential in engaging with immune cells, particularly colonic macrophages, and suppressing the synthesis of proinflammatory cytokines such as IL‐1, TNF‐α and IL‐6 144–146 .…”

Modulation of gut microbiota: a novel approach to enhancing the effects of immune checkpoint inhibitors

“…Certain bacteria have been identified to facilitate ICI responses and reduce ICI toxicities, including Akkermansia, Bifidobacterium, etc. 119 Chaput et al 25 showed that patients treated with ipilimumab with increased representation of Faecalibacterium and Firmicutes had increased efficacy of ICIs, as well as increased risk of developing colitis or other ICI-induced toxicities, which is known as the efficacy-toxicity coupling effect.…”

Liquid Biopsy in Lung Cancer: Biomarkers for the Management of Recurrence and Metastasis

“…It is known that the microbiome plays an important role in human health and disease by modulating a host's innate and adaptive immune system, immune responses, and metabolism, and by protecting from invading pathogens [235][236][237]. The tumor microenvironment (TME) influences cancer progression and therapy responses [238] and many recent studies have demonstrated associations between the TME and microbiota composition and responses to immune checkpoint inhibitors in cancer patients, including NSCLC patients, suggesting that modulation of the microbiota through diet, probiotics, and fecal microbiota transplantations (FMT) could improve treatment efficacy [238][239][240][241][242][243][244]. There is also a possibility that the lung microbiome change could be used as a biomarker for detecting clinical phenotypes [245].…”