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Innate Immune Mechanisms Contributing to Cancer Growth in Obesity

肥胖导致癌症生长的先天免疫机制

基本信息

批准号：
10706825
负责人：
EDGAR G. ENGLEMAN
金额：
$ 23.18万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10706825
关键词：
Acceleration Acids Address Adult Affect African American Asian Body mass index Breast Carcinoma Cancer Patient Cells Clinical Clinical Trials Collaborations Colon Carcinoma Colorectal Cancer Consultations Coupled Cytometry Data Detection Disease Ethnic Origin Fatty Acids Frequencies Functional disorder Future G-Protein-Coupled Receptors GTP-Binding Proteins Growth High Fat Diet High Prevalence Hispanic Hispanic Populations Human Immune Incidence Learning Lipids Macrophage Malignant Neoplasms Malignant neoplasm of gastrointestinal tract Malignant neoplasm of liver Malignant neoplasm of pancreas Malignant neoplasm of urinary bladder Maps Molecular Mus Non obese Not Hispanic or Latino Obese Mice Obesity Obesity associated cancer Oleic Acids Pancreatic Adenocarcinoma Patients Phenotype Play Population Primary carcinoma of the liver cells Production Race Risk Risk Factors Role Sampling Signal Transduction Surface TNF gene Testing Therapeutic Intervention Time Tissues Tumor Immunity Tumor-associated macrophages Tumor-infiltrating immune cells Weight cancer health disparity cytokine diet-induced obesity experience experimental study indexing innate immune mechanisms lipid metabolism malignant breast neoplasm molecular targeted therapies mouse model neoplasm immunotherapy neoplastic cell new therapeutic target novel obese patients obesogenic parent grant parent project single-cell RNA sequencing spatial relationship tumor tumor growth tumor metabolism tumor microenvironment

项目摘要

Supplement Project Summary Obesity (body mass index ≥30 kg/m2), which affects at least one-third of the U.S. population, is more prevalent among African American and Hispanic populations and increases the risks of both developing and dying from certain cancers. However, the cellular and molecular mechanisms underlying these risks are unknown. Our studies demonstrate that colorectal cancer (CRC) and other tumors grow considerably faster in diet-induced obese mice due to the immunosuppressive actions of the acid-sensing receptor, G-protein coupled 65 (GPR65), on tumor-associated macrophages (TAMs). In the parent project, we are analyzing the intracellular signals from GPR65 that alter TAM function and tumor growth in obese mice, identifying the mechanism by which a high-fat diet (HFD) promotes GPR65 signaling in TAMs, and assessing the effects of targeting GPR65 for tumor immunotherapy in obese and non-obese mice. Data from the parent project indicate that altered lipid metabolism is responsible for upregulating GPR65 expression on TAMs in the tumors of obese mice. Since the lipid profile in tumors of obese humans is nearly identical to that of tumors from obese mice, we believe there is a high likelihood that tumors from obese humans will display a similar immune profile. In the proposed supplement project, we will extend our studies to human cancers including CRC, hepatocellular carcinoma (HCC), pancreatic adenocarcinoma (PDAC) and breast carcinomas in order to test the hypothesis that GPR65 expression on TAMs is associated with obesity, altered TAM function and alterations of other immune cells in the tumor microenvironment. We further hypothesize that these effects of obesity on immune cells in cancer are equivalent in African American, Hispanic, Asian and non-Hispanic White populations and not determined on the basis of race or ethnicity. To analyze the tumors, we will use mass cytometry (CyTOF) to examine the frequencies, surface, and cytokine profiles of immune cells in the tumor, use single cell RNA sequencing (scRNA seq) to analyze the functional profiles of these cells and use CODEX to analyze the spatial relationships between TAMs and other immune cells. We will then compare the results between tumors from patients of different racial and ethnic backgrounds. The results of these experiments are expected to confirm both of our hypotheses and provide a strong rationale for future studies in which these hypotheses are tested in larger populations, and novel therapies targeting GPR65 are developed and evaluated in clinical trials.

补充项目总结