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Gasdermin E-mediated pyroptosis in promoting antitumor immunity and cancer treatment

Gasdermin E介导的焦亡促进抗肿瘤免疫和癌症治疗

基本信息

批准号：
10338167
负责人：
Ying Zhang
金额：
$ 11.22万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10338167
关键词：
Address Affect Antibodies Antigens Apoptosis Bioinformatics Blocking Antibodies Bone Marrow CASP3 gene CD8-Positive T-Lymphocytes CD8B1 gene Cancer Patient Caspase Cell Culture Techniques Cell Death Cell Maturation Cell physiology Chemicals Collaborations Communities Cross Presentation Cytometry Cytotoxic agent DNA Methylation DNA Modification Methylases Decitabine Dendritic Cells Dendritic cell tumor Drug Targeting Effectiveness Enzymes FDA approved Flow Cytometry Goals Hypermethylation Immune Immune response Immunity Immuno-Chemotherapy Immunologics Immunotherapeutic agent Immunotherapy Inflammatory Injections Investigation Laboratories Lead Lymphocyte Lytic Malignant Neoplasms Mediating Mediator of activation protein Memory Mentors Modeling Molecular Mus N-terminal Patients Pattern Phagocytes Pharmaceutical Preparations Phase Play Production Property Protein Kinase Proteins RIPK1 gene Research Research Personnel Resources Role Series Shapes Stress T cell response T-Lymphocyte T-cell inflamed Technology Testing Therapeutic Time Tissues Training Transgenic Mice Translational Research Tumor Immunity Tumor-Infiltrating Lymphocytes Tumor-associated macrophages Tumor-infiltrating immune cells VDAC1 gene Work antitumor effect cancer cell cancer immunotherapy cancer therapy career chemokine cytokine cytotoxic epigenetic silencing expectation immunoregulation improved inhibitor mouse model neoplastic cell novel strategies novel therapeutics promoter receptor recruit response single-cell RNA sequencing skills tumor tumor growth tumor immunology tumor microenvironment

项目摘要

Project Summary/Abstract The majority of cancers, which are immunologically “cold” with limited T cell infiltration, show abysmal response rates to immunotherapy. Novel strategies to enhance recruitment and functions of tumor-infiltrating lymphocytes (TIL) are urgently needed to improve cancer immunotherapy. How cancer cells die in response to stress, cytotoxic lymphocytes, and drugs has a profound impact on the immune landscape of cancer. While most cancer cell death has been viewed as noninflammatory, our recent study showed that pore-forming protein Gasdermin E (GSDME), when expressed in tumor cells, converts noninflammatory apoptosis to pyroptosis, a highly inflammatory form of programmed cell death. GSDME potently inhibits tumor growth and enhances the numbers and antitumor functions of CD8+ and NK TILs. The tumor-inhibitory effect of GSDME is mediated by TIL killing of GSDME+ target tumor cells, which can also trigger tumor cell pyroptosis. Our study suggests that promoting cancer cell pyroptosis has excellent potential to improve cancer immunotherapy, but it remains unclear how GSDME-induced pyroptosis boosts antitumor immunity. The proposed research aims to investigate how tumor GSDME expression shapes the tumor-infiltrating immune cells and their interactions to increase tumor immunity, and to develop a novel strategy to promote inflammatory cancer cell death, with the long-term goal to enhance immunotherapeutic efficacy for cancer patients. Specifically, I will study how damage-associated molecular patterns (DAMPs) produced by GSDME+ tumor cells modulate the composition, maturation, and functions of tumor-infiltrating dendritic cells (TIDCs) and tumor-associated macrophages (TAMs), key players to induce potent antitumor T cell response, by using CyTOF and inhibitors of DAMPs or their receptors (Aim 1). Aided by single cell (sc)RNA-seq and bone marrow chimeric mice, I will study how different TIDC subsets interact with CD8+ TILs to promote GSDME-mediated antitumor immunity (Aim 2). As many cancer cells epigenetically silence GSDME and RIPK3 (key mediator of necroptosis, another inflammatory form of cell death) via promoter hypermethylation, I will investigate whether the DNA methylation inhibitor decitabine could promote cancer cell pyroptosis and necroptosis to suppress tumor growth and enhance antitumor immunity (Aim 3). These studies will greatly advance our understanding of GSDME’s immunostimulatory mechanism and offer new opportunities to revitalizing immunotherapeutic efficacy for patients with uninflamed “cold” tumors. My career goal is to lead an independent academic laboratory addressing questions on cancer immunology and immunotherapy. In the K99 phase, I will take full advantage of the extensive resources at the vibrant research community of Harvard and the outstanding team of mentors and collaborators to receive comprehensive training in advanced technologies, bioinformatics, mouse models, and translational research, to further establish collaborations and sharpen my professional skills. The proposed training plan will serve as a superb roadmap that will lead me to my goal of succeeding as an independent investigator, and to make a difference in the lives of cancer patients.

项目总结/文摘