Treating colon cancer by regulating intestinal immunity through microbial metabolism

PROJECT SUMMARY
Colorectal cancer (CRC) is profoundly affected by the intestinal immune system and the intestinal microbiome,
which can exert both pro- and anti-cancer effects that operate alongside cell-intrinsic mutational events. Immune
cells produce reactive molecules and cytokines which contribute to epithelial mutagenesis and proliferation, and
immune cells infiltrate developing tumors and influence response to chemotherapy and anti-tumor
immunotherapy. Therapeutically modulating the immune system holds potential for transforming CRC outcomes,
but such interventions must be precisely targeted to specific signaling pathways, immune cell types and, ideally,
delivered locally. One promising source for such precision immunomodulatory targets are metabolites produced
by the intestinal microbiome, which have recently been shown to exert powerful effects on specific immune cell
types in the intestine. Exploiting the therapeutic potential of microbial metabolites requires: 1) basic knowledge
of the diet-microbe-metabolite-immune signaling network, 2) safe and effective means for localized metabolite
delivery, and 3) validated targets for defined therapeutic contexts. In this proposal, we will address these three
key gaps, with a unifying focus on a key population of anti-inflammatory T cells in the intestine: RORgt+ regulatory
T cells (RORgt+ Tregs). In Aim 1, we will dissect the mechanism of a previously unknown microbome-metabolite-
immune pathway by which the microbiome and dietary tryptophan regulate intestinal RORgt+ Treg populations.
In Aim 2, we will engineer a probiotic strain of E coli to serve as a general platform for localized delivery of
therapeutic metabolites; our initial goal will be to boost RORgt+ Tregs by overproducing the short-chain fatty acid
butyrate. In Aim3, we will evaluate the efficacy of elevating RORgt+ Tregs (via dietary butyrate) on key outcomes
for sporadic vs colitis-associated CRC in vivo. This project will deepen our understanding of metabolic
immunoregulation, develop novel probiotic strains for therapeutic metabolite delivery, and evaluate the role of
an important anti-inflammatory cell type in CRC.

Grant Number: 5R01CA259634-05
NIH Institute/Center: NIH
Principal Investigator: Nicholas Arpaia