Deciphering host-microbiome interactions in anti-cancer immunity

Introduction

Despite unprecedented clinical success, T cell-based immunotherapies present significant heterogeneity in response rates, often attributed to dampened activation and limited tumour infiltration of CD8+ T cells. Studies in mice and humans have shown that gut commensals can modulate anti-cancer immune responses dictating the efficacy of immunotherapy, but have failed to identify species that are consistently associated with improved patient prognosis.

Breakthrough Discovery

I recently made a breakthrough in our efforts to understand the host determinants that define microbiome-dependent cancer immunity. I discovered that a single micronutrient, vitamin D (vitD), enhances the ability of the gut microbiome to induce potent T cell-mediated immunity to cancer, dictating immunotherapy success in pre-clinical models.

Unlike any other study, I found that vitD modulates the function of the microbiome without significantly affecting its composition, diverging from a species-centric view of the microbiome to focusing on key host-microbiome interactions regulated by nutrient availability.

Project Overview

MICROBIOGUARD attempts to systematically dissect the multidirectional gut-immune-cancer axis. We first address a key question in the field: what defines a ‘good’ microbiome that promotes immunity to cancer?

Aims of the Proposal

1. Aim 1: Dissect the mechanisms by which vitD transforms the function of the gut microbiome with a focus on the identification of microbial-derived bioactive molecules.
2. Aim 2: Assess how these altered microbial functions interact with host cells bidirectionally to shape anti-cancer immunity.
3. Aim 3: Investigate if vitD enables the human microbiome to augment immunotherapy response.

Conclusion

Collectively, MICROBIOGUARD provides an unmatched opportunity to identify non-redundant microbiome-immune checkpoints that can be targeted to overcome immunotherapy resistance.