SUMMARY: Obesity is associated with increased risk for 13 cancers. Critical questions are how and to what extent underlying mechanisms of obesity-mediated increases in chronic inflammation may increase cancer risk in a failure of “protective immunity”. This knowledge gap represents an untapped opportunity that our multidis- ciplinary team is uniquely qualified to explore with a mission to improve understanding of cancer risk. We have previously shown obesity alters T cell and macrophage functions that could decrease anti-tumor protections and have expertise in human studies essential for this interdisciplinary challenge. Our objective is to identify associations in human subjects and test mechanisms of mediators of cancer risk in various pre-clinical models along an “obesitymicrobes metabolites protective immunity” axis. Our hypothesis is that obesity-altered gut microbes enhance cancer risk through dysregulated protective immunity that allows increased initiation. Aim 1 will define obesity-mediated dysregulation of microbial-derived metabolites and impacts on immune phe- notypes and protective immunity in human subjects at greater risk for cancer by examining diverse subjects 1a) of varied age and adiposity; and 1b) obese patients pre- and post- bariatric surgery. Donors will be drawn from the Memphis area, which offers a highly diverse population with 65% African Americans with a high inci- dence of obesity. Patient analyses will inform studies in complementary pre-clinical models to allow for mecha- nistic investigation to identify conserved mechanisms in the pre-cancer microenvironment. Aim 2 will deter- mine the impact of microbially-derived metabolites on cancer risk by examining immune cells in spontaneous transgenic models of breast cancer with established heterogeneity in latency, obesogenic response to high fat diet, circulating bile acids, and gut microbes. Aim 3 will test dietary administration of a specific microbially-de- rived metabolite or microbe on protective immunity in complementary carcinogenic and syngeneic models of obesity-mediated breast cancer, respectively. Human subject and murine model studies complemented by ex vivo and in vitro studies will test underlying mechanisms to determine how microbially-modified metabolites may impact immune-cancer cell crosstalk. Collaborative funds for cross-consortium activities are reserved for risk assessment across heterogenous lean and obese populations and models across aims to add synergistic impact to our findings through NCI’s Metabolic Dysregulation and Cancer Risk Program. In sum, outcomes will define beneficial microbially-derived metabolites that impact protective immunity to reduce cancer initiation. Thus, the strategy of this proposal is conceptually original, innovative, and significant to define conserved un- derlying mechanisms that suppress cancer risk. Findings generated will have high impact because the obesity- associated etiological impacts on risk will be heterogeneous and this study is designed to investigate those varied mechanisms to translate to better risk management to improve patient outcomes.

NARRATIVE: Obesity is broadly associated with both increased incidences of a variety of cancers and a chronic inflammatory state. Our interdisciplinary team with expertise in cancer, obesity, microbiome, immunometabolism will test if obesity-altered gut microbes enhance cancer risk through dysregulated protective immunity which leads to changes in the immune milieu that increase cancer cell transformation and initiation. These studies will increase understanding of obesity-associated cancer risk and point to potential interventions to alleviate this risk or treat existing cancers.