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: 10219207
• 负责人: Mark R Boothby
• 金额: $ 49.32万
• 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/10219207
• 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/antagonist; interest; interstitial; macromolecule; malignant breast neoplasm; molecular subtypes; molecular targeted therapies; neoplastic cell; novel; novel therapeutic intervention; programs; recruit; response; spatial relationship; success; targeted treatment; 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.

项目总结/摘要 乳腺癌是西方女性最常见的恶性肿瘤。尽管有佐剂和 分子靶向治疗显著改善某些分子亚型患者的生存率 三阴性/基底细胞样乳腺癌（TNBC）的预后仍然严峻， 这是由于缺乏对致癌驱动因子的识别。在寻找癌症易感性的过程中， 发现TNBC特别依赖于谷氨酰胺代谢，可能是由于- 谷氨酰胺转运蛋白ASCT 2/SLC 1A 5和谷氨酰胺酶GLS的调节，代表 谷氨酰胺消耗的限速步骤。尽管对靶向去乙酰氨基酶的兴趣 在TNBC中，尚不清楚谷氨酰胺代谢的全面抑制将如何影响免疫细胞， 肿瘤微环境，特别是考虑到快速增殖肿瘤浸润 淋巴细胞（TIL）需要氨解来提供用于细胞生长的大分子。 具体而言，肿瘤细胞和TIL之间对谷氨酰胺的竞争尚未被证实。 迄今为止，研究，但可能是重要的抗肿瘤免疫。 我们已经产生了初步的数据，提供了GLS特异性敲除的证据， 肿瘤细胞增加肿瘤间质液中的谷氨酰胺浓度， 细胞毒性CD 8 T淋巴细胞活性。上述效应在免疫缺陷的 这表明适应性免疫起着关键作用。此外，药理学 抑制谷氨酰胺转运蛋白ASCT 2，选择性靶向肿瘤细胞，同时增强 TIL功能。基于这些发现，我们假设（1）肿瘤细胞竞争TIL， 谷氨酰胺以维持其增殖程序，同时抑制抗肿瘤 免疫应答，和（2）选择性靶向肿瘤细胞中的谷氨酰胺代谢， 抗肿瘤免疫为了验证这些假设，我们将首先测试谷氨酰胺之间的竞争， 肿瘤细胞和TIL的竞争以及这种竞争如何影响肿瘤生长、转移和抗肿瘤 免疫反应（目标1）。我们还将明确如何代谢变化，在GLS损失具体 通过MALDI成像质量在肿瘤细胞中原位影响T细胞募集和活化 光谱法（目标2）。最后，我们将评估谷氨酰胺的体内药理学靶向 转运蛋白和转氨酶用于治疗TNBC（目的3）。该项目的成功将阐明 一个长期存在的问题是肿瘤之间是否存在谷氨酰胺的代谢竞争， 细胞和浸润淋巴细胞，并利用知识开发新的治疗方法， 治疗谷氨酰胺成瘾性癌症的策略。