Unlocking the Microbial Symphony: The Interplay of Human Microbiota in Cancer Immunotherapy Response

Abstract

Introduction: The emergence of cancer immunotherapy has revolutionized cancer treatment, offering remarkable outcomes for patients across various malignancies. However, the heterogeneous response to immunotherapy underscores the necessity of understanding additional factors influencing treatment efficacy. Among these factors, the human microbiota has garnered significant attention for its potential role in modulating immune response. Body: This review explores the intricate relationship between the human microbiota and cancer immunotherapy, highlighting recent advances and potential mechanisms underlying microbial influence on treatment outcomes.

Conclusion: Insights into the microbiome's impact on immunotherapy response not only deepen our understanding of cancer pathogenesis but also hold promise for personalized therapeutic strategies aimed at optimizing patient outcomes.

Keywords: cancer; immunotherapy; microbiome; microbiota.

Figure 1

Immune checkpoints and their role in immunosuppression and immune checkpoint inhibitor therapy. Immune checkpoints CTLA-4, PD-1, LAG-3, TIM-3, and TIGIT bind to their ligands on cancer cells, contributing to decreased T cell activity and immunosuppression. Immune checkpoint inhibitor therapy utilizes antibodies targeting these proteins and their ligands, disrupting their interactions and promoting anti-cancer immune activity. Created with BioRender.com.

Figure 2

The tumor microenvironment contains diverse elements that influence cancer progression and outcomes. Different populations of immune cells, fibroblasts, stromal components, and microbes work in tandem to maintain niches in the tumor that can potentially influence responses to treatment. Created with BioRender.com.

Figure 3

The microbiome influences outcomes in classical cancer treatment modalities. Gammaproteobacteria can convert gemcitabine into an inactive metabolite, reducing its efficacy in PDAC. Additionally, antibiotic depletion of the microbiome can reduce the efficacy of 5-FU and oxaliplatin. Oxaliplatin can work synergistically with resident gut microbiota that generate ROS that enhance the cytotoxicity of the drug. FMT studies have demonstrated that microbiomes that have been subjected to radiation can lead to poor prognosis and adverse events to radiotherapy. Conversely, it has been found that patient microbiomes that are enriched with Lactobacillus, Bifidobacterium, Lachnospiraceae, and Enterococcaceae have improved responses to radiotherapy and fewer adverse events, possibly due to the production of short-chain fatty acids (SCFAs) that promote anti-inflammatory pathways. Analyses of patient microbiomes have demonstrated a dynamic equilibrium between the gut and intra-tumor microbiomes that influence post-operative outcomes. Created with BioRender.com.

Figure 4

The microbiome influences ICI therapy outcomes. Fecal matter analysis of patients with melanoma demonstrated that responders to anti-PD-1 treatment had a microbiota that was enriched in Faecalibacterium and Clostridiales. Additionally, intratumor microbiomes that contained Lactobacillus reuteri showed improved responses to anti-PD-L1 therapy due to the metabolism of tryptophan into I3C. Antibiotic treatment of mice and patients is associated with diminished responses to ICI treatment, while certain genera such as Alistipes, Bifidobacterium, and Bacteroidales are associated with increased ICI effectiveness. Created with BioRender.com.