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.

项目摘要/摘要乳腺肿瘤很少通过化学疗法放射放射。存在残留疾病的原因有2个原因：肿瘤细胞1）避免凋亡，有丝分裂灾难和营养剥夺死亡； 2）避免免疫清除。我们的先前的研究已经确定，通过激活p53介导的抑制和感应程序，肿瘤细胞避免因有丝分裂灾难，凋亡和营养剥夺而死亡。我们显示了接受化学疗法的与p53突变体患者相比肿瘤。衰老细胞通过产生细胞因子和趋化因子来促进缓解（称为相关的秘密表型或SASP）。先前研究的弱点是未能识别处理过的，感觉肿瘤细胞如何避免免疫清除。在此提案中，我们提供了令人信服的初步数据，以解决这一弱点，并计划完全表征和调查针对细胞死亡进化的潜在治疗途径，因此支持免疫清除并改善生存率。在初步数据中，我们确定了一个非凡的 PD-L1在持续存在的残留疾病中的上调可能是通过与基质细胞相互作用而介导的表达保持在浮雕中，表明具有强大的选择压力。该项目的目的是确定机制并制定策略以专门针对免疫进化在通过进入感应的化学疗法中幸存下来的肿瘤细胞中。假设：基质干扰素伽马（IFNγ）在化学疗法的特定细胞子集中诱导PD-L1 治疗的感觉肿瘤。这些持续存在的感觉肿瘤细胞可以使用一种新型策略来瞄准结合了鼻溶剂来诱导免疫原性死亡，然后是免疫切除剂抑制剂。在AIM 1中，我们将使用小鼠乳腺肿瘤模型来确定PD-L1表达肿瘤细胞是否更大中继潜能比不表达PD-L1的同一处理肿瘤内的细胞，以及每个反应如何反应撤退。我们将表征表达PD-L1与不具有的细胞的基因表达差异。在AIM 2中，我们将确定体内PD-L1上调在感觉肿瘤细胞上所需的因素。我们将把乳腺肿瘤移植到缺乏特定免疫成分（例如T细胞）的同烯型小鼠中，用化学疗法治疗，并确定PD-L1表达和免疫环境的变化。在AIM 3中，初步数据显示，只有三分之一的感觉小鼠乳腺肿瘤对抗PD-L1做出了反应化疗后的治疗。我们将测试使用BH3模拟药物诱导免疫原性细胞死亡我们已经证明具有鼻溶性活性可以改善对免疫检查点抑制剂的反应。在AIM 4中，我们将使用人类乳腺癌标本前后的多重免疫组织化学染色化学疗法以确定在感觉肿瘤中是否诱导PD-L1表达。