The role of gut microbiome on the immunogenicity of immune hot neuroblastoma tumours
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.