权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Targeting mechanisms of immune evasion in chemotherapy-induced senescent cells

化疗诱导的衰老细胞免疫逃避的靶向机制

基本信息

批准号：
10364840
负责人：
James Jackson
金额：
$ 43.23万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-19 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10364840
关键词：
Address Aftercare Apoptosis Apoptotic Bioinformatics Breast Breast Cancer Model Breast Cancer Patient Cell Aging Cell Cycle Arrest Cell Death Cells Cessation of life Clinical Clinical Trials Combined Modality Therapy Data Effectiveness Failure Gene Expression Gene Expression Profile Genes Goals Growth Harvest Human Immune Immune Evasion Immune Targeting Immune checkpoint inhibitor Immunohistochemistry Immunologics Immunology Immunotherapy Interferon Type II Interferons Malignant Neoplasms Mammary Neoplasms Mediating Messenger RNA Mitotic Modeling Mouse Mammary Tumor Virus Mus Neoplasm Transplantation Nutrient Nutrient Depletion Oncologist Pathologic Patients Phagocytes Pharmaceutical Preparations Phenotype Population Production Proteins Relapse Research Research Design Residual Tumors Resistance Retreatment Sampling Series Signal Transduction Specimen Stains Stromal Cells T-Lymphocyte TP53 gene Testing Therapeutic Transplantation Tumor Escape Tumor-infiltrating immune cells Up-Regulation anti-PD-L1 anti-PD-L1 therapy cancer therapy cancer type checkpoint inhibition chemokine chemotherapy cytokine exhaustion immune clearance immunogenic cell death improved in vivo malignant breast neoplasm mimetics mouse model mutant neoplastic cell novel novel strategies novel therapeutics nutrient deprivation predicting response predictive signature pressure prevent programmed cell death ligand 1 programs response senescence single cell sequencing single-cell RNA sequencing statistics therapeutic target triple-negative invasive breast carcinoma tumor

项目摘要

Project Summary/Abstract Breast tumors are rarely eradicated by chemotherapy. Residual disease exists for 2 reasons: the tumor cells 1) avoid death from apoptosis, mitotic catastrophe, and nutrient deprivation; 2) avoid immune clearance. Our previous research has established that by activating p53-mediated programs of arrest and senescence, tumor cells avoid death by mitotic catastrophe, apoptosis, and nutrient deprivation. We showed chemotherapy treated breast cancer patients with p53 wild type tumors have dismal survival compared to patients with p53 mutant tumors. Senescent cells promote relapse by their production of cytokines and chemokines (termed the senescence associated secretory phenotype, or SASP). The weakness of prior research has been a failure to identify how the treated, senescent tumor cells avoid immune clearance. In this proposal, we present compelling preliminary data addressing this weakness, and plans to fully characterize and investigate potential therapeutic avenues that target the evasion of cell death, thus facilitating immune clearance and improving survival. In preliminary data, we identify a remarkable upregulation of PD-L1 in the persisting residual disease likely mediated through interactions with stromal cells, and expression is maintained in the relapse, suggesting a strong selective pressure. The goal of this project is to identify mechanisms and develop strategies to target immune evasion specifically in tumor cells that have survived chemotherapy by entering senescence. Hypothesis: Stromal interferon gamma (IFNγ) induces PD-L1 in a specific subset of cells in a chemotherapy- treated, senescent tumor. These persisting, senescent tumor cells can be targeted using a novel strategy that combines senolytic drugs to induce immunogenic cell death followed by immune checkpoint inhibitors. In Aim 1 we will use mouse mammary tumor models to determine if PD-L1 expressing tumor cells have greater relapse potential than cells within the same treated tumor that do not express PD-L1, and how each responds to retreatment. We will characterize gene expression differences in cells that express PD-L1 vs. those that do not. In Aim 2 we will identify the factors in vivo that are required for PD-L1 upregulation on senescent tumor cells. We will transplant mammary tumors into syngeneic mice that lack specific immune components such as T cells, treat with chemotherapy, and determine changes in PD-L1 expression and immune contexture. In Aim 3, preliminary data show only one third of senescent mouse mammary tumors responded to anti-PD-L1 therapy following chemotherapy. We will test if inducing immunogenic cell death with BH3 mimetic drugs we have shown to have senolytic activity can improve the response to immune checkpoint inhibitors. In Aim 4, we will use multiplex immunohistochemistry staining of human breast cancer specimens pre and post chemotherapy to determine if PD-L1 expression is induced in senescent tumors.

项目总结/文摘