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

• 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
• 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

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/摘要 乳腺肿瘤很少能通过化疗根除。残留疾病存在的原因有2个：肿瘤细胞1） 避免因细胞凋亡、有丝分裂灾难和营养缺乏而死亡; 2）避免免疫清除。我们 先前的研究已经证实，通过激活p53介导的停滞和衰老程序，肿瘤 细胞通过有丝分裂灾难、凋亡和营养剥夺避免死亡。我们发现化疗 与p53突变型乳腺癌患者相比，p53野生型乳腺癌患者的生存率低 肿瘤的衰老细胞通过产生细胞因子和趋化因子（称为细胞因子）促进复发。 衰老相关分泌表型或SASP）。 先前研究的弱点是未能确定经过治疗的衰老肿瘤细胞如何避免 免疫清除在本提案中，我们提出了解决这一弱点的令人信服的初步数据， 计划充分描述和研究潜在的治疗途径，以逃避细胞死亡为目标， 从而促进免疫清除并提高存活率。在初步数据中，我们发现了一个显著的 持续残留疾病中PD-L1的上调可能通过与基质细胞的相互作用介导， 并且表达在复发中保持，表明强烈的选择压力。 这个项目的目标是确定机制和发展战略，以针对免疫逃避具体 在化疗后存活下来的肿瘤细胞中，它们进入衰老期。 假设：基质干扰素γ（IFNγ）在化疗中诱导特定细胞亚群中的PD-L1- 治疗过的衰老肿瘤可以使用一种新的策略来靶向这些持续存在的衰老肿瘤细胞， 联合使用衰老清除药物诱导免疫原性细胞死亡，然后使用免疫检查点抑制剂。 在目标1中，我们将使用小鼠乳腺肿瘤模型来确定表达PD-L1的肿瘤细胞是否具有更大的 与不表达PD-L1的相同治疗肿瘤内的细胞相比， 再治疗我们将描述表达PD-L1的细胞与不表达PD-L1的细胞的基因表达差异。 在目标2中，我们将确定衰老肿瘤细胞上PD-L1上调所需的体内因素。 我们将把乳腺肿瘤移植到缺乏特定免疫成分（如T细胞）的同基因小鼠中， 用化疗治疗，并确定PD-L1表达和免疫结构的变化。 在目标3中，初步数据显示只有三分之一的衰老小鼠乳腺肿瘤对抗PD-L1抗体有反应。 化疗后的治疗。我们将测试是否用BH 3模拟药物诱导免疫原性细胞死亡， 已经显示具有衰老清除活性可以改善对免疫检查点抑制剂的反应。 在目的4中，我们将使用多重免疫组织化学染色的人乳腺癌标本前，后， 化疗以确定衰老肿瘤中是否诱导PD-L1表达。