Defining the role of microenvironmental ammonia in colorectal cancers

定义微环境氨在结直肠癌中的作用

基本信息

批准号：
10463578
负责人：
Hannah Noelle Bell
金额：
$ 0.62万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
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：
2021-08-01 至 2022-08-02
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10463578
关键词：
APC mutation Advanced Development Advanced Malignant Neoplasm Ammonia Antitumor Response Attenuated Automobile Driving Bioenergetics Carcinoma Cell Proliferation Cell physiology Cells Chemicals Clinic Clinical Colon Colon Carcinoma Colonic Neoplasms Colorectal Cancer Colorectal Neoplasms Data Data Analyses Diagnosis Drug Metabolic Detoxication Dysplasia Effectiveness Epithelial Epithelial Cells Gases Gene Expression Genetic Genetic Transcription Genotype Goals Growth Hepatic Hyperammonemia Immune Immune Evasion Immune response Immunotherapeutic agent Immunotherapy In Vitro Incidence Institution Intervention K-ras mouse model KRAS2 gene KRASG12D Laboratories Malignant Neoplasms Mentors Metabolic Metabolism Metastatic Neoplasm to the Liver Metastatic Neoplasm to the Lung Modeling Multiomic Data Mus Mutation Neoplasm Metastasis Nuclear Nude Mice Oncology Organ Ornithine Patients Physicians Physiological Process Proteomics Public Health RNA analysis Regimen Regulation Resistance Role Scientist Signal Transduction Specific qualifier value Supplementation Survival Rate T cell response T-Cell Proliferation T-Lymphocyte TP53 gene Tamoxifen Testing Training Tumor-Derived Tumor-infiltrating immune cells Urea Waste Products Work adenoma aminoacid biosynthesis anti-tumor immune response base cancer cell cancer diagnosis carcinogenesis career cell growth cell type colon cancer cell line colon cancer patients colon carcinogenesis cytokine driver mutation immune checkpoint blockers improved metabolomics mortality mouse model multiple omics mutant neoplastic cell prevent promoter response transcriptional reprogramming transcriptome sequencing transcriptomics treatment response tumor tumor growth tumor microenvironment tumor progression tumor-immune system interactions urea cycle wasting

项目摘要

Abstract: Colorectal cancer is a grave public health concern with only a 14% survival rate for Stage IV diagnosis, and few viable treatment options. Colon tumors are composed of a cadre of cells and the interplay between these cells is critical for tumor growth. Previous work shows that the initial immune-tumor dynamic is robustly anti- tumor, but that this anti-tumor response is attenuated as tumors progress. Immunotherapies that re-activate the anti-tumor response are currently widely used in many cancers. Although colon tumors have a robust immune infiltrate, immunotherapies have largely failed for unclear reasons. Further, cancer cells are known to reprogram cellular metabolism to meet their proliferative needs. Cancer cell proliferation produces metabolic waste products that can be re-purposed to maintain cellular bioenergetic needs. However, it is clear that the vast majority of the metabolic byproducts accumulate in the tumor microenvironment. There is a critical gap regarding how metabolic waste products interact with the immune infiltrates. My preliminary data demonstrates that KRAS mutant colon tumors have an increase in ammonia waste that accumulates in the tumor microenvironment. Moreover, my preliminary data shows that T cell proliferation and anti-tumor response is significantly inhibited at biologically relevant concentrations that have been detected in colon tumors, while other cell types are largely unaffected. I have also shown that chemical ammonia detoxification reduces tumor growth in a T cell dependent manner. This suggests that ammonia waste contributes to the attenuated anti- tumor immune response commonly observed in colon cancer. data I hypothesize that increased microenvironmental ammonia in advanced cancers is central to maintaining an immunosuppressive state by altering T cell function. The long-term goal of this proposal is to understand how colorectal tumors modulate the microenvironment through metabolic products to decrease the effectiveness of the immune response. Understanding this will advance the development of immune-based therapeutic regimens. Based on these observations, the experimental focus of this proposal is on the regulatory role of tumor-generated ammonia on T cell function. Aim 1 will determine whether KRAS mutation is driving ammonia accumulation in advanced cancers. Aim 2 will explore how detoxifying ammonia in the tumor microenvironment increases the T cell immune response, using both genetic and chemical interventions. Preventing this negative hetero- cellular cross talk between the tumor and T cells may improve the efficacy of immunotherapy approaches in colorectal cancer. Importantly, pursuing the aims specified in this proposal will provide rigorous scientific and clinical training at a highly ranked and well supported institution. This type of institutional, facility, and mentor support will further my path towards a career as a physician scientist with an active oncology laboratory.

抽象的：大肠癌是一个严重的公共卫生问题，IV阶段诊断仅14％，并且很少有可行的治疗选择。结肠肿瘤由细胞干部和这些细胞的相互作用组成细胞对于肿瘤生长至关重要。先前的工作表明，初始免疫肿瘤动态是牢固的抗肿瘤，但随着肿瘤的进展，这种抗肿瘤反应会减弱。重新激活的免疫疗法目前，抗肿瘤反应在许多癌症中广泛使用。虽然结肠肿瘤有强大的免疫浸润，免疫疗法在很大程度上因不清楚的原因而在很大程度上失败了。此外，已知癌细胞重编程细胞代谢以满足其增殖需求。癌细胞增殖产生代谢可以重新使用以维持细胞生物能量需求的废物。但是，很明显绝大多数代谢副产品在肿瘤微环境中积累。有关键的差距关于代谢废物如何与免疫浸润物相互作用。我的初步数据证明了 KRAS突变结肠肿瘤的氨废物增加，积聚在肿瘤中微环境。此外，我的初步数据表明T细胞增殖和抗肿瘤反应是在结肠肿瘤中检测到的生物学相关浓度下，显着抑制其他细胞类型在很大程度上不受影响。我还表明，化学氨解毒会减少肿瘤以T细胞依赖的方式生长。这表明氨废物有助于衰减的抗肿瘤免疫反应通常在结肠癌中观察到。数据我假设增加了高级癌症中的微环境氨对于维持免疫抑制至关重要通过更改T细胞功能来陈述。该提议的长期目标是了解结直肠肿瘤通过代谢产物调节微环境以降低免疫的有效性回复。了解这将推动基于免疫的治疗方案的发展。基于这些观察结果，该提案的实验重点是肿瘤生成的调节作用 T细胞功能上的氨。 AIM 1将确定KRAS突变是否正在推动氨的积累高级癌症。 AIM 2将探索肿瘤微环境中氨的排毒如何增加使用遗传和化学干预措施，T细胞免疫反应。防止这种负面的异质肿瘤和T细胞之间的细胞横向交谈可能会提高免疫疗法方法的功效结直肠癌。重要的是，追求本提案中指定的目标将提供严格的科学和在一个高度且支持良好的机构中进行的临床培训。这种机构，设施和导师支持将进一步成为我在积极肿瘤实验室担任医师科学家职业的道路。