Investigating the influence of the aged microbiome on the immune response to cancer

Project Outline

Over the last decade, immunotherapy has transformed the clinical management of cancer, but responses remain limited to subsets of patients. The intestinal microbiome has emerged as a key regulator of cancer immunity and the efficacy of immunotherapy. Specific bacterial populations have been shown to correlate with response to immune checkpoint inhibitors (ICI), chemo and radiotherapy, and manipulation of the microbiota can potentially enhance treatment outcome.  Both the immune system and the microbiome are known to change with age: T cells undergo a functional decline (immune senescence), and microbial diversity is known to alter and may contribute to the pathogenesis of inflammatory disorders. Despite this, the impact of age on the efficacy of anti-cancer therapies is poorly understood, and pre-clinical models investigating ageing are vastly underexplored.  

This project seeks to examine the impact of age on the microbiome and immune response to cancer. Our preliminary data demonstrate that responses to immunotherapy approaches are significantly reduced in aged mice and that this is linked to changes in the T cell repertoire within the tumour microenvironment (TME). The project will use a unique faecal biobank from young and old mice, including longitudinal samples collected over 1.5 years, to explore the relationship between age, microbiome and cancer immunity. Age-related changes in microbial diversity will be determined and correlated with response to immunotherapy approaches. The impact of the aged microbiome on the immune response to cancer will be assessed using faecal microbial transplant and extensive profiling of the T cell landscape of the TME using flow, mass cytometry, immunohistochemistry and RNA sequencing.   

The outcome of this project will be to provide novel insights into the impact of ageing on the microbiome and generation of effective immune responses to cancer, that have potentially important implications for the translation of immunotherapy approaches to elderly cancer patients. 

Applications for this project are now open. Please complete your application on The University of Manchester website.