Electronic Thesis and Dissertation Repository

Thesis Format

Monograph

Degree

Master of Science

Program

Pathology

Supervisor

Maleki Vareki, Saman

2nd Supervisor

Burton, Jeremy P.

Co-Supervisor

Abstract

Inducing mismatch repair (MMR) deficiency in poorly immunogenic tumours has been shown to stimulate anti-tumour immunity, leading to improved survival and immune checkpoint inhibitor (ICI) response. Recent data suggest that factors beyond tumour genomics, including host-specific factors such as gut microbiota, play a role in modulating anti-tumour immune responses. Preclinical and clinical evidence suggests that gut microbial composition affects cancer progression and the efficacy of ICIs. Furthermore, antibiotic treatment has been shown to induce gut dysbiosis and promote tumourigenesis in cancer patients; however, little is known about their role in immunologically cold tumours rendered hot through induced MMR deficiency. Here, we elucidated the impact of antibiotic-induced gut dysbiosis on anti-tumour immune responses and tumour progression in an induced MMR deficient (idMMR) murine neuroblastoma (NB) model. Antibiotic exposure resulted in bacterial composition alterations and a decrease in microbial diversity. It was linked to increased NB tumour growth and altered immune responses locally and systemically. Importantly, anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) therapy was shown to counteract the negative impacts of antibiotic-mediated microbiota dysbiosis on tumour growth. These findings highlight the critical role of gut microbiota alongside tumour genomics in shaping anti-tumour immune responses and the potential of integrating microbiota modulation to enhance ICI outcomes in hard-to-treat cancers.

Summary for Lay Audience

Tumours with genetic features that make them more visible to the immune system have been shown to grow at a reduced rate. These tumours also respond better to immunotherapy, a cancer treatment that leverages the body's immune system to fight against the tumour. However, recent findings show that cancer progression is determined not only by the cancer's genetic characteristics but also by factors in the patient's body, like the bacteria in their gut. Both laboratory experiments and patient studies have demonstrated that the bacteria residing in the gut can influence how effectively the immune system combats cancer and responds to immunotherapy. Cancer patients receiving antibiotics may negatively impact the populations of bacteria in their gut and experience lower survival rates, and as a result, immunotherapy may not work well for them. In this thesis, we studied how gut bacteria affect immune responses against tumours made more detectable by the immune system. We found that antibiotics, which changed the types and diversity of gut bacteria, caused these tumours to grow larger. The negative effect of antibiotics on gut bacteria resulted in fewer effective and more fatigued immune cells responsible for fighting cancer cells. A type of immunotherapy known as anti-CTLA-4 therapy prevented the increase in tumour growth despite the effects of antibiotics. Our findings suggest that the bacteria in our gut play a crucial role in cancer progression, which could have important implications for immunotherapy treatments.

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Available for download on Sunday, June 28, 2026

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