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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

基本信息

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
项目类别：
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

项目摘要

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