Deciphering host-microbiome interactions in anti-cancer immunity

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. 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.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? Aim 1 of this proposal will dissect the mechanisms by which vitD transforms the function of the gut microbiome with a focus on identification of microbial-derived bioactive molecules. We will then assess how these altered microbial functions interact with host cells bidirectionally to shape anti-cancer immunity (Aims 1/2). We will broaden our findings and determine how vitD-microbiome-immune interactions impact cancer development. Finally, we will investigate if vitD enables human microbiome to augment immunotherapy response (Aim 3). Collectively, MICROBIOGUARD provides an unmatched opportunity to identify non-redundant microbiome-immune checkpoints that can be targeted to overcome immunotherapy resistance.