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.

项目概要/摘要 尽管结直肠癌（CRC）治疗取得显着改善，但结直肠癌患者的预后 转移性结直肠癌（mCRC）仍然很差，中位总生存期约为 30 个月。 免疫疗法如免疫检查点阻断（ICB）代表了一种新的治疗方法 多种癌症，包括微卫星不稳定性高 (MSI-H) 的转移性结直肠癌 (mCRC)。然而，ICB 治疗几乎没有显示出 或大约 95% 的微卫星稳定 (MSS) mCRC 患者没有临床活性。我们和其他人 已经表明，施用生酮饮食（KD）或酮体β-羟基丁酸酯（βHB）， 在小鼠肿瘤模型中增强 ICB 对 CRC 的抗癌作用。然而KD/βHB能否改善 ICB 治疗伴 MSS 的 CRC 尚不清楚。此外，改变生酮作用对 免疫抑制肿瘤微环境（TME）仍有待定义，代表了我们的主要差距 了解肿瘤免疫抵抗。 癌症相关成纤维细胞（CAF）是肿瘤基质细胞的主要成分，在 肿瘤抑制性 TME。我们已经证明，生酮下调是 CRC TME 的一个标志。激活 致癌信号（例如 WNT 和 KRAS）的作用会降低 CRC 的生酮作用。恢复生酮 抑制 CAF 中的有氧糖酵解活性并抑制组蛋白脱乙酰酶 1 (HDAC1)/KLF5 依赖性 CAF 增殖和细胞因子的表达和分泌。重要的是，我们证明 KD 改善了 免疫抑制性 TME，表现为 CD8+ T 细胞和 NK 细胞浸润增加以及 M2 减少 巨噬细胞群，并增强 ICB 的功效。我们的研究结果证明了一个以前未知的 TME 中从头生酮、代谢改变和 CAF 功能下调的关联 确定癌症生酮作为潜在的免疫治疗靶点。基于这些新颖的发现，我们 假设下调生酮作用有助于增殖和免疫抑制作用 CAF 从而对 CRC TME 进行重新编程，从而导致 ICB 耐药和 CRC 进展。我们的长期 目标是识别癌症和/或基质区室中的异常代谢，可用于 改善 mCRC 患者的治疗。为了检验我们的中心假设，我们组装了一个高度 合作团队在结直肠癌进展和治疗、肿瘤代谢、肿瘤 免疫和肿瘤生酮，以及计划进行的实验，以确定改变的影响 CRC 中免疫抑制 TME 的生酮作用，描绘 CAF 代谢的生酮控制， TME 中的增殖和功能效力，并定义靶向生酮代谢对 TME 的影响 ICB 对 CRC 的疗效。最终，我们的发现将： i) 彻底改变我们的 CRC TME 概念 免疫抵抗； ii) 显着推进有关 KD/βHB 影响的范式； iii) 可以提供 针对生酮代谢失调的新型结直肠癌治疗策略。