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Project 3: Modulation of the head and neck tumor immune microenvironment by targeting the TAM family of receptors

项目3：通过靶向TAM受体家族调节头颈肿瘤免疫微环境

基本信息

批准号：
10673984
负责人：
DERIC L WHEELER
金额：
$ 36.55万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-02 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10673984
关键词：
Aftercare Automobile Driving Binding Biological Response Modifiers CD8-Positive T-Lymphocytes Cancer cell line Cells Cellular Indexing of Transcriptomes and Epitopes by Sequencing Cessation of life Clinic Clinical Clinical Trials Data Dose Drug Targeting Environment FDA approved Family Growth Head and Neck Cancer Head and Neck Neoplasms Human Immune Immune checkpoint inhibitor Immune system Immunocompetent Immunodeficient Mouse Immunological Models Immunologics Immunophenotyping Immunotherapeutic agent Immunotherapy Individual Infiltration Inflammatory Knock-out Knowledge Laboratories Leucocytic infiltrate Macrophage Malignant Neoplasms Measures Medical Oncologist Microscopy Modeling Molecular Mus Myelogenous Myeloid-derived suppressor cells Newly Diagnosed Operative Surgical Procedures Outcome Pathologist Patients Phenotype Pilot Projects Play Population Pre-Clinical Model Production Radiation Radiation Oncologist Radiation therapy Receptor Protein-Tyrosine Kinases Receptor Signaling Recurrence Reporting Resistance Role Scientist Series Solid Neoplasm Survival Rate T cell infiltration T-Lymphocyte TYRO3 gene Testing Therapeutic Translating Translations United States Universities Wisconsin Work anti-PD1 therapy axl receptor tyrosine kinase cell killing checkpoint therapy chemotherapy conventional therapy cytokine experimental study head and neck cancer patient immune cell infiltrate immune checkpoint blockade immunoregulation in vivo inhibitor inhibitor therapy innovation insight monocyte mouse model neoplastic cell novel novel drug class novel therapeutics precursor cell programmed cell death ligand 1 receptor recruit response safety and feasibility targeted agent translational physician translational study tumor tumor growth tumor-immune system interactions

项目摘要

ABSTRACT – PROJECT 3 The primary objective of this proposal is to examine the cooperation of the receptor tyrosine kinases Axl and MerTK as drivers of an immunosuppressive tumor immune microenvironment (TIME) and if targeting tumor Axl and MerTK simultaneously can turn this suppressive TIME (cold) to an inflammatory TIME (hot). Immune checkpoint inhibitors have gained FDA approval in the management of Head and Neck Cancer (HNC). Despite established benefit, clinical trials have highlighted that less than 20% of HNC patients respond to this promising new class of inhibitors. This suggests a gap in knowledge and represents a major clinical hurdle as we try to understand how best to enhance the immune system to better outcomes. Recent work from our laboratory has shown that Axl and MerTK cooperate to drive an immunologically cold environment. In addition, targeting tumor Axl or MerTK individually versus a new class of drug that targets both Axl and MerTK simultaneously, called INCB081776, revealed that dual targeting of Axl and MerTK was superior to targeting Axl or MerTK alone in immune models. Furthermore, INCB081776 potently inhibited tumor growth in immunocompetent mice but not in immunodeficient mice, demonstrating that a functional immune system is important. Treatment of syngeneic models with INCB081776 was associated with dose-related increases in the percentage of tumor-infiltrating effector CD4+ and CD8+ T cells as well as macrophages with the M1 phenotype. In addition, INCB081776 decreased the percentage of intratumoral M2 macrophages and monocytic myeloid– derived suppressor cell (M-MDSC) immune cell populations. Together, this suggests that simultaneous targeting of Axl and MerTK is superior in producing an anti-tumor (hot) TIME. Collectively, our data suggests that tumor Axl and MerTK work together to drive HNC via tumor intrinsic and tumor extrinsic (immune) mechanisms. We hypothesize that tumor Axl and MerTK cooperate to produce a myeloid-suppressive TIME, through regulation of immune mediators, and that therapeutic strategies targeting tumor Axl and MerTK simultaneously will shift the immune TIME from cold to hot resulting in greater tumor kill. In Aim 1 we intend to define how tumor Axl and MerTK cooperate to regulate immune mediators that promote this cold TIME by recruiting myeloid derived precursor cells and driving M2 polarization ultimately leading to T cell suppression. In Aim 2 we intend to determine the impact of targeting tumor Axl and MerTK simultaneously in HNC syngeneic mouse models and measure the impact on immune cell infiltration (Macrophages and T cells) and tumor growth. Finally, in Aim 3, we propose a clinical trial to utilize this promising new drug, INCB081776, in patients and determine if it can shift a cold TIME to a hot TIME and if this impacts tumor growth in humans. To carry out these studies we have assembled a strong team of molecular biologists, translational physician-scientists, medical oncologist, radiation oncologist, pathologists and biostatisticians. This investigative strategy holds great promise for translation to the clinic and brings innovation by leveraging new molecular insights to a significant existing problem in HNC.

摘要-项目3