Effect of tumor cell glutamine metabolism on anti-tumor immunity in TNBC

TNBC肿瘤细胞谷氨酰胺代谢对抗肿瘤免疫的影响

• 批准号: 10430078
• 负责人: Mark R Boothby
• 金额: $ 48.33万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-17 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10430078
• 关键词: Adjuvant; Affect; Allografting; Amino Acids; Biological Assay; Biological Models; Breast Cancer Cell; Breast Cancer Model; CD8-Positive T-Lymphocytes; Cancer Prognosis; Cell physiology; Cells; Clinical Trials; Coculture Techniques; Collaborations; Consumption; Data; Exhibits; Glutaminase; Glutamine; Glycolysis; Growth; Image; Immune; Immunotherapy; Implant; In Situ; In Vitro; Infiltration; Intercellular Fluid; Knock-out; Knowledge; Lymphocyte; Lymphocyte Count; Lymphocyte Function; Malignant Epithelial Cell; Malignant Neoplasms; Maps; Mass Spectrum Analysis; Measures; Metabolic; Metabolism; Modeling; Mus; Neoplasm Metastasis; Nutrient; Oncogenic; Patient-derived xenograft models of breast cancer; Patients; Pharmacology; Phenotype; Play; Positioning Attribute; Positron-Emission Tomography; Proliferating; Refractory; Role; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; System; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Therapeutic Intervention; Toxic effect; Transgenic Model; Tumor Escape; Tumor Immunity; Tumor-Infiltrating Lymphocytes; Up-Regulation; Woman; adaptive immunity; anti-tumor immune response; base; cancer cell; cancer imaging; cell growth; cytotoxic CD8 T cells; glucose metabolism; improved; in vivo; indexing; inhibitor; interest; interstitial; macromolecule; malignant breast neoplasm; mass spectrometric imaging; molecular subtypes; molecular targeted therapies; neoplastic cell; novel; novel therapeutic intervention; programs; recruit; spatial relationship; success; targeted treatment; treatment response; treatment strategy; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor microenvironment; uptake

PROJECT SUMMARY/ ABSTRACT Breast cancer is the most common malignancy among western women. Although adjuvant and molecularly targeted therapies significantly improve patient survival in some molecular subtypes of breast cancer, the prognosis of triple-negative/basal-like breast cancer (TNBC) remains grim, due to lack of identification of oncogenic drivers. In searching of cancer vulnerability, it was discovered that TNBC is especially dependent on glutamine metabolism, likely due to up- regulation of the glutamine transporter, ASCT2/SLC1A5, and glutaminase, GLS, representing the rate-limiting steps in glutamine consumption. Despite the interest in targeting glutaminolysis in TNBC, it is unclear how global inhibition of glutamine metabolism will affect immune cells in the tumor microenvironment, particularly given that rapidly proliferating tumor infiltrating lymphocytes (TILs) require glutaminolysis to supply macromolecules for cell growth. Specifically, the competition between tumor cells and TILs for glutamine has not been investigated thus far, but is likely to be important for anti-tumor immunity. We have generated preliminary data providing evidence that knockout of GLS specifically in tumor cells increases glutamine concentration in the tumor interstitial fluid and enhances cytotoxic CD8 T lymphocyte activities. The above effects are abrogated in immune-deficient mice, suggesting that adaptive immunity plays a critical role. In addition, pharmacologic inhibition of the glutamine transporter, ASCT2, selectively targeting tumor cells while enhancing TIL function. Based on these findings, we hypothesize that (1) tumor cells outcompete TILs for glutamine to sustain their proliferative programs while simultaneously suppressing antitumor immune response, and (2) selectively targeting glutamine metabolism in tumor cells enhances antitumor immunity. To test these hypotheses, we will first test glutamine competition between tumor cells and TILs and how this competition affects tumor growth, metastasis, and anti-tumor immune responses (Aim 1). We will also define how metabolic changes in GLS loss specifically in tumor cells impact T cell recruitment and activation in situ by MALDI-imaging mass spectrometry (Aim 2). Finally, we will evaluate in vivo pharmacological targeting of glutamine transporter and glutaminase for treating TNBC (Aim 3). The success of the project will elucidate a long-standing issue whether there is a metabolic competition for glutamine between tumor cells and infiltrating lymphocytes, and leverage the knowledge for developing new therapeutic strategies for treatment of glutamine-addicted cancer.

项目摘要/摘要 乳腺癌是西方妇女中最常见的恶性肿瘤。虽然佐剂和 分子靶向疗法在某些分子亚型中显着改善了患者的存活率 在乳腺癌中，三阴性/基底样乳腺癌（TNBC）的预后仍然严峻， 由于缺乏对致癌驱动因素的识别。在寻找癌症脆弱性时， 发现TNBC尤其取决于谷氨酰胺代谢，这可能是由于上升 谷氨酰胺转运蛋白，ASCT2/SLC1A5和谷氨酰胺酶的调节，代表GLS 谷氨酰胺消耗的限速步骤。尽管有兴趣靶向谷氨酰胺溶解 在TNBC中，尚不清楚全球抑制谷氨酰胺代谢将如何影响免疫细胞 肿瘤微环境，特别是考虑到快速增殖的肿瘤浸润 淋巴细胞（TILS）需要谷氨酰胺溶解以提供大分子以进行细胞生长。 具体而言，肿瘤细胞和tils之间的谷氨酰胺竞争尚未 迄今已研究，但可能对抗肿瘤免疫很重要。 我们已经生成了初步数据，提供了证据表明GLS的敲除 肿瘤细胞增加肿瘤间质液中的谷氨酰胺浓度并增强 细胞毒性CD8 T淋巴细胞活性。上述效果在免疫缺陷中被废除 小鼠表明自适应免疫起着至关重要的作用。另外，药理学 抑制谷氨酰胺转运蛋白ASCT2，有选择地靶向肿瘤细胞，同时增强 TIL功能。基于这些发现，我们假设（1）肿瘤细胞胜过 谷氨酰胺以维持其增殖计划，同时抑制抗肿瘤 免疫反应，（2）选择性靶向肿瘤细胞中的谷氨酰胺代谢增强 抗肿瘤免疫。为了检验这些假设，我们将首先测试 肿瘤细胞和TIL以及该竞争如何影响肿瘤的生长，转移和抗肿瘤 免疫反应（目标1）。我们还将定义GLS损失的代谢变化如何 在肿瘤细胞中，通过MALDIMI-IMIGAGE质量影响T细胞的募集和原位激活 光谱法（AIM 2）。最后，我们将评估谷氨酰胺的体内药理靶向 用于治疗TNBC的转运蛋白和谷氨酰胺酶（AIM 3）。该项目的成功将阐明 长期存在的问题是否存在肿瘤之间的谷氨酰胺竞争 细胞和浸润淋巴细胞，并利用开发新治疗的知识 治疗谷氨酰胺成瘾癌症的策略。