Sumiki’s Acid, a de novo Dietary Compound Generated from Food Processing, Reprograms NK Cells for Cancer Immunoprevention

University Of Chicago, Chicago IL

Investigators

Abstract

PROJECT SUMMARY/ABSTRACT Immunoprevention has emerged as a promising approach to reducing cancer risk, with most efforts in vaccines development, or repurposing of immune checkpoint inhibitors (ICIs). However, whether dietary small molecule substances as effective immunomodulators for cancer immunoprevention is largely unknown. Emerging evidence suggests a link between the de novo substances generated from food processing and immunomodulation and a reduced risk of certain cancers. Considering the vital immunosurveillance roles of NK cell against tumorigenesis, we hypothesize that certain de novo substances generated from food processing may act as bioactive compounds (named deFPBioC) with immunomodulatory functions, exerting a direct and specific influence on NK cells and related immunity to inhibit tumorigenesis. we assembled a novel deFPBioC library and systematically examined their direct effects on NK cell-dependent cytotoxicity against cancer cell. Sumiki’s acid (SKA), generated from Millard Reaction during food processing by hearing, or microbiota biosynthesis, was identified as top candidate, which can significantly enhance the activation and cytotoxic functions of both primary human NK cells and mouse NK cells. The oral administration of SKA boosts NK- mediated anti-tumor immunity in various therapeutic mouse models, which encourages me to further determine its potential as a cancer-preventive agent in spontaneous GEMM and carcinogen-induced colon cancer models (Aim 1), and elucidate the underlying molecular mechanism (Aim 2). In addition, I aim to perform medicinal chemistry studies for newly designed molecules with improved potency, and bioengineering of gut-microbiota for SKA in situ production for more effective and sustain cancer-preventive effects (Aim 3). The scientific knowledge and technical skills gained from these studies as well as my research training plan will help me develop a unique research direction and facilitate transition into independence. I will extend my independent research by focusing on the gut-resident immunity, investigating how de novo metabolites generated from microbiota-mediated nutrient processing (named MicroNutriMetabolites, MNMs) regulate diverse gut residential immune cells and related immunity response for colon cancer immunoprevention.