The gut microbiota and immune checkpoint inhibitors

Abstract

Although immunotherapy has been remarkably effective across multiple cancer types, there continues to be a significant number of non-responding patients. A possible factor proposed to influence the efficacy of immunotherapies is the gut microbiome. We discuss the results and implications of recent research on the relationship between the gut microbiome, our immune systems, and immune checkpoint inhibitor therapies including anti-CTLA-4 Ab and anti-PD-1 Ab. While the investigations all exhibit interesting results and conclusions, we find little congruence in the specific bacteria that were found favorable for antitumor responses. It is unclear whether the inconsistencies are due to differential approaches in study design (pre-clinical or clinical subjects, anti-CTLA-4 Ab or anti-PD-1 Ab), experimental methods and measurements (metagenomics sequencing and clustering variations) or subject population dynamics (differential cancer types and baseline characteristics). Moreover, we note studies regarding particular bacterial commensals and autoimmune diseases, which challenge findings from these investigations. We conclude that with the current research, clinical investigators can appreciate the critical role of gut microbiota in mediating immunostimulant response. However, prospective research exploring the biochemical mechanisms which commensal bacteria communicate with each other and the immune system is imperative to understand how they can be adjusted properly for higher immunotherapy response.

Human microbial ecology and the rising new medicine

“…Higher gut microbiome diversity and the dominance of Ruminococcaceae and Bifidobacterium longum were found in responders versus nonresponders, in melanoma patients enrolled in anti-PD-1 therapy (47). Besides, germ-free mice and antibiotic-treated mice models have shown an impaired efficacy of anti-CTLA-4 antibody treatment (48), which proves a direct role of the gut microbiota.…”

Mechanisms of checkpoint inhibition-induced adverse events

“…While these studies point to an evident link between the microbiome and response/toxicity, as recently reviewed by Humphries and Daud , there is significant difficulty in interpreting studies related to the microbiome in checkpoint inhibition. Literature implicates a wide range of bacteria, highlighting the significant variation that can be found between microbiome studies.…”

Endocrine complications of cancer immunotherapy

“…The trials on pre-treatment identification of possible future therapy-driven adverse outcomes, defining possible predicting biomarkers to identify at-risk patients and enable early adverse reaction detection, are still ongoing [16,17]. Additionally, trials on the influence of external factors, such as diet, smoking status, or gut microbiome, are also in progress [18,19].…”

“…Trwają badania nad możliwością oceny wyjściowej pacjenta pod kątem spodziewanej toksyczności immunoterapii i znalezienia biomarkerów, które pozwolą na identyfikację zagrożonych chorych oraz wczesne wykrycie możliwych działań niepożądanych [16,17]. Toczą się również badania dotyczące związku między nasileniem działań ubocznych immunoterapii a paleniem tytoniu czy dietą, a ściślej składem flory bakteryjnej jelit (gut microbiome) [18,19]. Jak wspomniano, powikłania immunoterapii mogą dotyczyć każdego narządu, występują z różną częstością w zależności od stosowanego schematu leczenia i pojawiają się w różnym czasie od rozpoczęcia immunoterapii.…”