Role of the Gut Microbiome in Cancer Immunotherapy Efficacy and Side Effects

Gut microbiome plays an important role in host health and disease, influencing various physiological processes, including immune responses. Its role becomes particularly significant in cancer immunotherapy, where the microbiome can shape both the efficacy and side effects of immune checkpoint inhibitor (ICI) therapies. However, the intricate interactions between microbiota composition, immune modulation, and ICI therapy remain incompletely understood. This thesis mainly investigated how gut microbiota dysbiosis affects immune cells, ICI-induced gut inflammation, and therapy outcomes, focusing on cytotoxic T-lymphocyte-associated protein (CTLA-4) and programmed cell death protein 1 (PD-1) blockade. The research examined how gut microbiota dysbiosis influences T cell populations in various intestinal compartments during CTLA-4 blockade therapy, the connection between specific microbiota compositions and inflammatory responses, and whether bacterial taxa can predict these responses. Additionally, the study explored how gut microbiota modulation impacts both the efficacy and toxicity of anti-CTLA-4 therapy in tumour-bearing mice and the role of gut bacteria-derived lipopolysaccharide (LPS) in anti-PD-1 therapy. Using an antibiotic-disrupted murine model with tumour burden, flow cytometry revealed increased T regulatory cell (Treg)/CD8+ T effector cell (Teff) ratios in the small intestines and elevated thymus-derived Treg (tTreg)/peripherally induced Treg (pTreg) ratios in the large intestine after anti-CTLA-4 therapy. In dysbiotic mice without tumours, the same therapy decreased mesenteric Treg populations and increased CD8+ Teffs in small intraepithelial lymphocytes. Histological assessment and lipocalin-2 measurement were used to evaluate anti-CTLA-4-induced gut inflammation. 16S rRNA sequencing identified specific bacterial taxa associated with gut toxicity (Dubosiella and genera from Lachnospiraceae) or protection (UBA7173 and Paramuribaculum). Genera from Lachnospiraceae and Oscillospiraceae were linked to reduced ICI efficacy, as evidenced by larger tumours. Using polymyxin B to eliminate LPS-producing Gram-negative bacteria and TAK-242 to inhibit TLR4 signalling in MC38 tumour-bearing mice, the study demonstrated that hexa-acylated LPS enhances anti-PD-1 efficacy via TLR4 signalling, whereas penta-acylated LPS has minimal effects. These findings suggest that gut microbial composition and LPS acylation patterns may serve as predictive biomarkers for immunotherapy response. In conclusion, this study reveals a complex interplay between gut microbiota, immune cells, and immune checkpoint blockade, affecting both therapeutic efficacy and toxicity. Understanding these mechanisms offers novel insights for optimising cancer immunotherapy and minimising side effects through microbiome-based interventions.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2025

Author dc:creator

• Xia, Wangmingyu

Advisor dc:contributor.advisor

• Pedicord, Virginia

• immunotherapy
• microbiology
• LPS

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/82a7a0a0-e557-4110-a9a2-345f1f02aca2/download
• https://creativecommons.org/licenses/by-nc/4.0/

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.119603

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/386356