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

• 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
• 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

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.

项目摘要/摘要 尽管结直肠癌（CRC）的治疗显着改善，但患者的预后 转移性CRC（MCRC）仍然很差，总体存活率中位数约为30个月。 免疫疗法（例如免疫检查点封锁（ICB））代表了一种新型的热方法 包括具有微卫星不稳定性高（MSI-H）的MCRC在内的各种癌症。但是，ICB治疗几乎没有 或在大约95％的微卫星稳定（MSS）MCRC患者中没有临床活性。我们和其他人 已经表明，给予生酮饮食（KD）或酮体β-羟基丁酸（βHB）， 在小鼠肿瘤模型中增强了ICB对CRC的抗癌作用。但是，KD/βHB是否可以改善 对于具有MSS的CRC的ICB治疗尚不清楚。此外，改变生酮的影响对 免疫抑制性肿瘤微环境（TME）仍有待定义，代表了我们的主要差距 了解肿瘤免疫抗药性。 癌症相关的成纤维细胞（CAFS）是肿瘤基质细胞的主要成分，在 肿瘤抑制TME。我们已经表明，下调的生酮发生是CRC TME的标志。激活 致癌信号传导（例如Wnt和Kras）的CRC中下降。生酮发生的恢复 抑制CAF中有氧糖酵解活性，并抑制组蛋白脱乙酰基酶1（HDAC1）/KLF5依赖CAF 增殖和细胞因子的表达和分泌。重要的是，我们表明KD改善了 免疫抑制性TME，如CD8+ T细胞和NK细胞浸润增加并改善M2所指出的那样 巨噬细胞种群，并提高ICB的效率。我们的发现证明了以前未知的 TME中下调的DE从头生酮发生，代谢改变和CAF功能的关联，并且 鉴定出癌症生酮是潜在的免疫治疗靶标。基于这些新颖的发现，我们 假设下调的生酮发生有助于 CAFS，因此对CRC TME进行了重编程，这会导致ICB抗性和CRC进展。我们的长期 目的是确定可用于用于癌症和/或基质室内的异常代谢 改善MCRC患者的治疗。为了检查我们的中心假设，我们已经组装了一个高度的 在CRC进展和治疗，肿瘤代谢，肿瘤方面具有重要专业知识的合作团队 免疫力和肿瘤生酮发生以及计划的实验，这些实验将决定改变的影响 CRC中免疫抑制性TME的酮症发生，描述CAF代谢的生酮控制， TME的增殖和功能效力，并定义了靶向生酮代谢对靶向的影响 ICB对CRC的功效。最终，我们的发现将：i）彻底改变我们的CRC TME概念和 免疫敏感； ii）显着提高了KD/βHB影响的范例； iii）可能会提供 新型CRC治疗策略通过靶向失调的生酮代谢。