Role of progenitor exhausted CD8 T cells and the progenitor niche in anti-PD1 efficacy

祖细胞耗尽的 CD8 T 细胞和祖细胞生态位在抗 PD1 功效中的作用

• 批准号: 10682523
• 负责人: Alexander Huang
• 金额: $ 55.05万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10682523
• 关键词: Acceleration; Address; Aftercare; Antigens; Biometry; Blood; CD8-Positive T-Lymphocytes; Cancer Patient; Cells; Chronic; Clinical; Clinical Trials; Clone Cells; Collection; Data; Dendritic Cells; Development; Dose; Equilibrium; Failure; Frequencies; Genetic Transcription; Goals; Homeostasis; Human; Immunofluorescence Immunologic; Immunology; Impairment; Inflammation; Knowledge; Malignant Neoplasms; Minority; Modeling; Neoadjuvant Therapy; Outcome; PD-1 blockade; Participant; Pathology; Patients; Population; Positioning Attribute; Production; Proliferating; RNA; Research Personnel; Resolution; Role; Signal Transduction; Stress; Structure; Study Subject; Supporting Cell; T cell differentiation; T cell infiltration; T cell receptor repertoire sequencing; T cell response; T-Cell Depletion; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Time; Translating; Viral Cancer; Virus Diseases; anti-PD-1; anti-PD1 therapy; anti-tumor immune response; cell type; clinical efficacy; clinically relevant; combinatorial; cytokine; exhaust; experience; immune checkpoint blockade; improved; lymphoid structures; melanoma; neoplastic cell; novel therapeutics; preclinical study; preservation; prevent; progenitor; programs; response; self-renewal; stem cell niche; stem cells; tertiary lymphoid organ; transcriptomics; tumor; tumor eradication

Project Summary Anti-PD-1 therapy reinvigorates exhausted CD8 T cells, which can lead to complete tumor eradication as early as 3 weeks. Yet, despite robust T cell reinvigoration in >78% of patients, less than 40% are cured. The goal of this proposal is to understand why robust reinvigoration of exhausted CD8 T cells by αPD-1 therapy does not necessarily translate to clinical efficacy. Exhausted CD8 T cells (TEX) are a major cell type responding to PD-1 blockade. We and others have shown that αPD-1 therapy (αPD-1) reinvigorates exhausted CD8 T cells, as defined by enhanced proliferation and cytokine production. TEX are heterogeneous with progenitor and terminally differentiated TEX that have different roles in anti-tumor immune responses. Progenitor TEX (ProgEX) replenish terminally differentiated TEX (TermEX), which in turn provide anti-tumor activity. Thus, similar to stem cells, ProgEX represent a reservoir for CD8 T cell responses against the tumor. Importantly, it is the ProgEX, rather than TermEX, that respond to αPD-1 and almost exclusively contribute to the early burst of CD8 T cell reinvigoration. Reinvigoration of TEX results in accelerated differentiation of ProgEX to TermEX, resulting in a numerically greater pool of TermEX and improved tumor control. However, at the same time, the accelerated differentiation induced by αPD-1 places increased stress on ProgEX homeostasis. This raises the possibility that a ProgEX niche is key for providing the cells and signals necessary to prevent the depletion of ProgEX, and may prove crucial for the efficacy of PD-1 blockade. Our central hypothesis is that depletion of ProgEX after αPD-1 impairs clinical efficacy and that a tumor- associated niche is important in maintaining the pool of ProgEX. In Aim 1, we will test the hypothesis that αPD-1 results in enhanced differentiation of ProgEX and that that depletion of ProgEX is associated with clinical progression. We will use combinatorial tetramers and single cell RNA+TCR sequencing to understand how αPD-1 alters the pool of melanoma-specific ProgEX, and how the size of ProgEX pool in turn, impacts the clinical efficacy of αPD-1. In Aim 2, we test the hypothesis that tertiary lymphoid structures serve as a tumor- associated niche for ProgEX, and that increased number or size of ProgEX niches after αPD-1 is associated with the preservation of ProgEX and clinical efficacy. We will use multiparameter immunofluorescence and spatial transcriptomics to define the cellular composition of the ProgEX niche, the transcriptional circuits utilized by ProgEX in the niche, and the importance of the ProgEX niche in preserving the pool of ProgEX.

项目摘要 抗PD-1治疗使耗尽的CD8 T细胞重新焕发活力，这可能导致肿瘤尽早完全根除 作为3周。然而，尽管78%的患者T细胞恢复了活力，但只有不到40%的患者被治愈。的目标是 这项建议是为了理解为什么αPD-1疗法对耗尽的CD8T细胞没有强大的重振作用 必然转化为临床疗效。 耗竭性CD8T细胞(TeX)是PD-1阻断后的主要细胞类型。我们和其他人已经展示了 αPD-1疗法(αPD-1)重振疲惫的CD8T细胞，其定义是促进增殖和 细胞因子的产生。Tex是异质性的，具有不同的祖先和终末分化的Tex 在抗肿瘤免疫反应中的作用。祖细胞TeX(ProgEX)补充终末分化TeX(TermEX)， 这反过来又提供了抗肿瘤活性。因此，与干细胞类似，ProgEX代表CD8 T细胞的储存库 对肿瘤的反应。重要的是，是ProgEX，而不是TermEX，对αPD-1和 CD8T细胞的早期活化几乎是独一无二的。重振Tex的成果是 加快了ProgEX到TermEX的差异化，从而增加了TermEX的数量并提高了性能 肿瘤控制。但与此同时，αPD-1位点诱导的加速分化作用增强 压力对ProgEX动态平衡的影响。这增加了这样一种可能性，即ProgEX利基是提供细胞和 防止ProgEX耗尽所需的信号，并可能被证明对PD-1阻断的疗效至关重要。 我们的中心假设是，αPD-1后ProgEX的耗尽会削弱临床疗效，并且肿瘤- 相关的生态位对维持ProgEX的池很重要。在目标1中，我们将检验假设 αPD-1导致肿瘤分化增强，其缺失与临床 进步。我们将使用组合四聚体和单细胞RNA+TCR测序来了解 αPD-1改变黑色素瘤特异性预后的池，以及预后池的大小反过来如何影响临床 αPD-1的疗效。在目标2中，我们测试了第三级淋巴结构作为肿瘤的假设- 与αPD-1相关的ProgEX生态位，以及ProgEX生态位数量或大小的增加与 ProgEX的保存及临床疗效。我们将使用多参数免疫荧光和空间 转录组学来定义ProgEX利基的细胞组成，转录电路由 ProgEX在利基中的地位，以及ProgEX生态位在保护ProgEX池中的重要性。