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Targeting the Immunosuppressive Tumor Microenvironment for Colorectal Cancer Treatment

针对结直肠癌治疗的免疫抑制肿瘤微环境

基本信息

批准号：
10748123
负责人：
Bernard Mark Evers
金额：
$ 40.03万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10748123
关键词：
3-hydroxy-3-methylglutaryl-coenzyme A Aerobic Biological Models CD34 gene CD8-Positive T-Lymphocytes CXCL6 gene Cancer Control Cancer Etiology Carbohydrates Cessation of life Characteristics Clinical Colorectal Cancer Cytotoxic T-Lymphocytes Down-Regulation Enzymes Fatty acid glycerol esters Fibroblasts Genetically Engineered Mouse Glycolysis Glycolysis Inhibition Goals Growth HDAC1 gene Histone Deacetylase Histone Deacetylase Inhibitor Human Immune response Immunosuppression Immunotherapeutic agent Immunotherapy In Vitro Infiltration KRAS oncogenesis KRAS2 gene Ketone Bodies Macrophage Malignant Neoplasms Mediating Metabolic Metabolism Metastatic Neoplasm to the Lung Microsatellite Instability Microsatellite Repeats Modeling Molecular Mus Natural Killer Cells Oncogenes Oncogenic PD-1 blockade PPAR gamma Patients Play Population Production Proliferating Publishing Repression Resistance Role Signal Transduction Stromal Cell-Derived Factor 1 Stromal Cells Stromal Neoplasm Techniques Technology Testing Therapeutic Treatment Protocols Tumor Immunity Tumor Tissue United States anti-PD1 therapy anti-cancer beta catenin beta-Hydroxybutyrate c-myc Genes cancer cell cancer therapy chemokine colon cancer patients colorectal cancer progression colorectal cancer treatment cytokine experimental study immune checkpoint blockade immune resistance improved in vivo innovation ketogenesis ketogenic diet ketogentic metabolomics metastatic colorectal mouse model multidisciplinary neoplastic novel novel therapeutic intervention patient derived xenograft model patient prognosis programs restoration single-cell RNA sequencing stable isotope therapeutically effective treatment strategy tumor tumor metabolism tumor microenvironment tumor-immune system interactions tumorigenesis

项目摘要

Project Summary/Abstract Despite notable improvements in colorectal cancer (CRC) treatment, the prognosis of patients with metastatic CRC (mCRC) remains poor, with a median overall survival of approximately 30 months. Immunotherapy such as immune checkpoint blockade (ICB) represents a novel therapeutic approach for a variety of cancers including mCRC with microsatellite instability-high (MSI-H). However, ICB therapy shows little or no clinical activity in approximately 95% of patients with microsatellite-stable (MSS) mCRC. We and others have shown that administration of either a ketogenic diet (KD) or the ketone body β-hydroxybutyrate (βHB), enhances the anticancer effects of ICB for CRC in mouse tumor models. However, whether KD/βHB can improve ICB therapy for CRCs with MSS is not known. Moreover, the impact of altered ketogenesis on the immunosuppressive tumor microenvironment (TME) remains to be defined and represents a major gap in our understanding of tumor immunoresistance. Cancer associated fibroblasts (CAFs), the major component of tumor stromal cells, play a critical role in the tumor suppressive TME. We have shown that downregulated ketogenesis is a hallmark in CRC TME. Activation of oncogenic signaling (e.g., WNT and KRAS) decreases ketogenesis in CRCs. Restoration of ketogenesis inhibits aerobic glycolytic activity in CAFs and inhibits histone deacetylase 1 (HDAC1)/KLF5 dependent CAF proliferation and cytokine expression and secretion. Importantly, we showed that KD improves the immunosuppressive TME, as noted by increased CD8+ T cell and NK cell infiltration and decreased M2 macrophage populations, and enhances the efficacy of ICB. Our findings demonstrate a previously unknown association of downregulated de novo ketogenesis, metabolic alteration and CAF functions in the TME and have identified cancer ketogenesis as a potential immunotherapeutic target. Based on these novel findings, we hypothesize that downregulated ketogenesis contributes to the proliferation and immunosuppressive effects of CAFs and thus, reprograms the CRC TME, which leads to ICB resistance and CRC progression. Our long-term goal is to identify aberrant metabolism within the cancer and/or stromal compartments that can be used to improve the treatment of patients with mCRC. To examine our central hypothesis, we have assembled a highly collaborative team with significant expertise in CRC progression and treatment, tumor metabolism, tumor immunity and neoplastic ketogenesis, and planned experiments which will determine the impact of alterations of ketogenesis on the immunosuppressive TME in CRC, delineate ketogenic control of CAF metabolism, proliferation, and functional potency in the TME, and define the impact of targeting ketogenic metabolism on the efficacy of ICB for CRC. Ultimately, our findings will: i) revolutionize our concept of CRC TME and immunoresistance; ii) significantly advance paradigms regarding the effects of KD/βHB; and iii) may provide a novel CRC treatment strategy by targeting dysregulated ketogenic metabolism.

项目总结/文摘