Imaging tumor and T cell responses to metabolic and immune modulation therapy

成像肿瘤和 T 细胞对代谢和免疫调节治疗的反应

基本信息

批准号：
10192675
负责人：
JASON Arthur KOUTCHER
金额：
$ 65.01万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-20 至 2022-09-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10192675
关键词：
Adjuvant Affect Animal Cancer Model Animals Biological Markers Breast Cancer Patient Breast Cancer Treatment CD3 Antigens CD3E gene CD8-Positive T-Lymphocytes CD8B1 gene CTLA4 gene Cell Separation Cell physiology Cells Cellular Metabolic Process Characteristics Clinical Clinical Data Combined Modality Therapy Cytotoxic T-Lymphocytes Data Data Set Dendritic Cells Disease Exclusion Fluorescence Gene Expression Gene Expression Profiling Genes Glycolysis Goals Harvest Human Image Imaging Techniques Immune Immune checkpoint inhibitor ImmunoPET Immunocompetent Immunofluorescence Immunologic Immunohistochemistry Immunologic Monitoring Immunosuppression Immunotherapy In Vitro Infiltration Inflammation Lactate Transporter Lactic acid Link MCT-1 gene Magnetic Resonance Imaging Magnetic Resonance Spectroscopy Mammary Neoplasms Memorial Sloan-Kettering Cancer Center Messenger RNA Metabolic Metabolism Metastatic breast cancer Modeling Monitor Multimodal Imaging Mus Natural Killer Cells Neoadjuvant Therapy Neoplasm Metastasis Operative Surgical Procedures PD-1/PD-L1 Patients Penetration Pharmacology Positioning Attribute Positron-Emission Tomography Prediction of Response to Therapy Probability Prognosis Pyruvate Resistance Solid Neoplasm T cell response T-Lymphocyte Therapeutic Treatment Effectiveness Treatment Failure Tumor Immunity Tumor-infiltrating immune cells aggressive breast cancer anti-CTLA4 anti-PD-1 anti-PD-1/PD-L1 base cancer imaging cell motility cell type cellular imaging clinical translation clinically relevant effectiveness evaluation extracellular imaging modality immune checkpoint immune checkpoint blockade immunogenicity immunomodulatory therapies immunoregulation improved in vivo inhibitor/antagonist lactate dehydrogenase A macrophage malignant breast neoplasm man mouse model neoplastic cell non-invasive imaging novel overexpression programmed cell death protein 1 responders and non-responders response success therapeutic target trafficking treatment response treatment strategy triple-negative invasive breast carcinoma tumor tumor metabolism tumor microenvironment tumorigenic uptake

项目摘要

PROJECT SUMMARY/ABSTRACT Purpose of the project. This application focuses on the use of imaging to better understand, reverse, and monitor immune suppression and metabolism in murine models of aggressive/metastatic breast cancer. High LDH-A and monocarboxylate transporters 1 and 4 (MCT-1 and MCT-4) have been linked to poor prognosis, and greater metastatic potential. Based on clinical analyses of GEO and MSKCC’s cBio Portal: i) tumors with increased expression of genes involved in lactate metabolism are more aggressive and have poor survival, and ii) there is an inverse correlation between the expression of glycolysis genes and immune-related genes. These data support our hypothesis: that high rates of tumor glycolysis leads to a lactic acid-rich tumor microenvironment (TME) with the exclusion of T cells, resulting in more aggressive tumors with a propensity to form metastases. We further hypothesize that reversal of the T cell exclusion with metabolic inhibitors will render tumors that are resistant to immune modulation with checkpoint blockade (CTLA-4, PD-1) to be responsive to the treatment, due to repopulation of T cells within the tumor microenvironment. Here, we propose to use multimodal imaging to explore the mechanisms by which metabolic and immune modulation therapy reverse the restriction and inactivation of cytotoxic T cells in clinically relevant murine models of aggressive breast cancer. We plan to: 1) characterize in vivo changes in tumor lactate and T cell infiltration during LDH-A and MCT-1/4 inhibition; 2) evaluate the responses to adjuvant and neo-adjuvant single and combination therapy (metabolic inhibition and “checkpoint” blockade in vivo); 3) validate the imaging results by assessing correlations between glycolytic biomarkers and T cell infiltration using ex vivo immunofluorescence (IF), immunohistochemistry (IHC), and fluorescence-assisted cell sorting (FACS); and 4) assess the potential for clinical translation. The translational goal is two-fold: 1) to induce regression in primary and metastatic breast cancer, by increasing tumor penetration and effector function of cytotoxic T cells, and 2) to monitor treatment response by non-invasive imaging. Experimental Strategy. We have established several murine models of aggressive breast cancer in immune competent host animals. In Aim 1, in vitro and in vivo studies will define how tumor-cell metabolism affects T cell function, and identify a “therapeutic window” for optimizing the magnitude and timing of T cell repopulation of aggressive murine breast tumors following LDH and MCT pharmacologic inhibition. In Aim 2, metabolic and immune-PET imaging will monitor how changes in the TME (induced by anti-LDH and anti-MCT treatment) affect T cell infiltration and function. Based on Aim 1 and 2 studies, an “optimized” lactate inhibition treatment strategy (established in Aims 1 and 2) will be combined with immune checkpoint blockade (anti-PD1 and anti- CTLA4) and assessed in Aim 3. Imaging will be used to quantitate tumor lactate, the conversion of hyperpolarized 13C-pyruvate to lactate, glycolysis (reflected in FDG uptake) and the trafficking of CD8+ T cells.

项目摘要/摘要项目的目的。该应用程序着重于使用成像来更好地理解，逆转和监测侵袭性/转移性乳腺癌的鼠模型中的免疫抑制和代谢。高的 LDH-A和单羧酸盐转运蛋白1和4（MCT-1和MCT-4）与预后不良有关，和更大的转移潜力。基于GEO和MSKCC CBIO门户网站的临床分析：i）肿瘤随着涉及刀具代谢的基因表达的增加，代谢更具侵略性，并且较差生存和ii）糖酵解基因的表达与免疫相关的表达之间存在反相关基因。这些数据支持我们的假设：肿瘤糖酵解的高速率导致富含乳酸的肿瘤微环境（TME）排除T细胞，导致更具侵略性的肿瘤有望形成转移。我们进一步假设，用代谢抑制剂排除T细胞的逆转将通过检查点封锁（CTLA-4，PD-1）抗免疫调节的肿瘤为由于对肿瘤微环境中T细胞的重生，对治疗的反应很快。在这里，我们建议使用多模式成像探索代谢和免疫的机制调节疗法逆转了临床相关鼠中细胞毒性T细胞的限制和失活侵略性乳腺癌的模型。我们计划：1）表征乳酸和T细胞体内变化 LDH-A和MCT-1/4抑制期间的浸润； 2）评估调整和新辅助单一的响应和联合疗法（代谢抑制和体内“检查点”阻滞）； 3）验证成像通过评估糖酵解生物标志物与T细胞浸润之间的相关性，结果使用离体免疫荧光（IF），免疫组织化学（IHC）和荧光辅助细胞分选（FACS）；和4）评估临床翻译的潜力。翻译目标是两个方面：1）诱导主要的回归和转移性乳腺癌，通过增加细胞毒性T细胞的肿瘤渗透和效应子功能，2）通过非侵入性成像监测治疗反应。实验策略。我们已经在免疫中建立了几种侵袭性乳腺癌的鼠模型主管动物。在AIM 1中，体外和体内研究将定义肿瘤新陈代谢如何影响T 细胞功能，并确定一个“治疗窗口”，以优化T细胞重新群的大小和时间 LDH和MCT药理学抑制后侵略性鼠乳腺肿瘤的侵袭性。在AIM 2中，代谢和免疫-PET成像将监测TME的变化（由抗LDH和抗MCT治疗诱导）影响T细胞浸润和功能。基于目标1和2的研究，“优化”的抑制作用治疗策略（AIM 1和2中建立）将与免疫障碍物封锁（抗PD1和抗 - CTLA4）并在AIM 3中进行了评估。成像将用于定量肿瘤裂缝，转化的转换超极化13C-丙酮酸裂解，糖酵解（反映在FDG摄取中）和CD8+ T细胞的运输。