Evaluation of T follicular regulatory cells as novel cellular targets of cancer immunotherapy

滤泡调节性 T 细胞作为癌症免疫治疗新细胞靶点的评估

• 批准号: 10737557
• 负责人: Simon Eschweiler
• 金额: $ 10.25万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10737557
• 关键词: ATAC-seq; Adoptive Transfer; Affect; Antibodies; Antigens; Antitumor Response; Automobile Driving; CD8-Positive T-Lymphocytes; CTLA4 gene; Cells; Cellular immunotherapy; Colitis; Colon; Combined Modality Therapy; DNA Binding; Data; Development; Dose; Enhancers; Epithelial Cells; Evaluation; Exhibits; Frequencies; Gene Expression Profile; Generations; Genes; Genetic Engineering; Genetic Transcription; Half-Life; Human; Immune; Immunology; Immunosuppression; Immunotherapy; Impairment; Infiltration; Link; Maintenance; Malignant Neoplasms; Modeling; Molecular; Mus; Nature; Neoadjuvant Therapy; Non-Malignant; Organ; Pathogenicity; Pathway interactions; Patients; Phosphatidylinositols; Phosphotransferases; Placebo Control; Primary Neoplasm; Property; Randomized; Regimen; Regulatory T-Lymphocyte; Role; Skin; Solid; Solid Neoplasm; T cell response; T-Lymphocyte Subsets; Testing; Therapeutic; Tissues; Toxic effect; Translating; Treatment Efficacy; Tumor Immunity; Tumor Tissue; anti-CTLA4; anti-PD1 therapy; antitumor effect; cancer immunotherapy; cancer type; cell type; cellular targeting; chromatin immunoprecipitation; cohort; draining lymph node; gastrointestinal epithelium; genetic approach; immune checkpoint blockade; immune-related adverse events; immunoregulation; improved; in vivo; inhibitor; insight; keratinocyte; melanoma; mouse model; neoantigens; novel; pharmacologic; phase II trial; precursor cell; programmed cell death protein 1; programs; protein expression; response; secondary lymphoid organ; selective expression; single-cell RNA sequencing; standard care; stem; survival outcome; targeted treatment; tertiary lymphoid organ; therapy development; transcription factor; transcriptomics; tumor; tumor growth; tumor microenvironment

Project Summary Immune checkpoint blockade (ICB) targeting CTLA-4 or PD-1 rapidly assumed its role as a standard treatment for solid tumors and can lead to dramatic, long-lasting responses; nonetheless, fewer than 30% of patients respond to monotherapy with either agent. Combination therapy results in better long-term survival outcomes, but also causes more frequent and severe immune-related adverse events (irAEs). Several novel immunotherapies are currently being explored to evaluate their anti-tumor capacity. Crucially however, most of these targets suffer from on-target, off-cell effects, as other immune cell types can express high levels of these molecules. Hence, as low overall response rates, off-cell effects and widespread immune related toxicity severely limit both treatment efficacy and monotherapy and combination therapy options, there is urgent need to develop novel immunotherapy targets that exhibit a more restricted expression profile. We have recently demonstrated that PD-1+ follicular regulatory T (TFR) cells were prevalent in tumor tissues of several cancer types in humans and mice, and that they were critical cellular determinants of anti-PD-1 treatment efficacy. TFR cells were primarily located within tertiary lymphoid structures (TLS) and exhibited superior suppressive capacity and in vivo persistence when compared to regulatory T (TREG) cells, suggesting a key role for TFR cells in impairing patient survival and impeding immunotherapy treatment efficacy. While we have shown that intratumoral TFR cells derive from TREG precursor cells, the mechanisms and transcription factors (TFs) that are driving this differentiation step are largely unknown. In Aim1, we propose to employ single-cell RNA-seq, single-cell ATAC-seq and micro- scaled ChIP assays to fully characterize the transcriptomic signatures of tumor-infiltrating TREG cells, transitioning (4-1BB+) TREG cells and TFR cells. Elucidating the enhancer profiles in different developmental stages of TREG to TFR differentiation is likely to provide crucial insights into the TFs that instruct this differentiation step. These analyses will define genes and TFs that are pivotal for the heightened suppressive capacity of TFR cells, as well as for their maintenance or differentiation. Strategies to deplete TREG cells or to curb their functionality with the aim of enhancing anti-tumor immunity are being intensively investigated. Crucially however, most of these approaches are based on antibodies (i.e., ADCC-optimized for TREG cell depletion; i.e. anti-CTLA-4), which have an inherently long half-life in vivo, thus increasing the likelihood of causing irAEs. Conversely, our data imply that alternative dosing regimens of Phosphoinositide 3-kinase δ (PI3Kδ) inhibitors might offer a pathway to target TFR cells more specifically. We propose that PI3Kδ represents a novel and appealing immunotherapy target in solid tumors. In Aim 2 and Aim 3, we will assess whether alternative dosing regimens of PI3Kd inhibitors can be utilized to effectively and safely exploit the immunomodulatory impact of PI3Kδ inhibitors in solid cancers and whether a transient depletion or inhibition of TFR cells might suffice to restrict the immunosuppressive milieu in the tumor and thus drive anti-tumor immunity without causing toxicity.

项目摘要 针对CTLA-4或PD-1的免疫检查点阻断(ICB)迅速成为一种标准治疗方法 对于实体肿瘤，可以导致戏剧性的、持久的反应；然而，只有不到30%的患者 对任何一种药物的单一治疗都有反应。联合治疗会带来更好的长期生存结果， 但也会导致更频繁和更严重的免疫相关不良事件(IrAE)。几部小说 目前正在探索免疫疗法，以评估它们的抗肿瘤能力。然而，至关重要的是，大多数 这些靶点受到靶点上和细胞外效应的影响，因为其他免疫细胞类型可以表达高水平的这些 分子。因此，由于总应答率低，细胞外效应和普遍存在的免疫相关毒性严重 限制治疗效果以及单一疗法和联合疗法的选择，迫切需要开发 新的免疫治疗靶点表现出更受限制的表达谱。我们最近展示了 PD-1+滤泡调节性T(TFR)细胞在人类多种肿瘤组织中的表达 和小鼠，它们是抗PD-1治疗效果的关键细胞决定因素。转铁蛋白受体细胞主要是 位于三级淋巴结构(TLS)内，并在体内显示出优越的抑制能力 与调节性T(Treg)细胞相比，TFR细胞在受损患者中发挥了关键作用 存活并阻碍免疫治疗疗效。虽然我们已经证明肿瘤内的TFR细胞来源于 在Treg前体细胞中，驱动这一分化步骤的机制和转录因子(TF) 在很大程度上是未知的。在AIM1中，我们建议使用单细胞RNA-SEQ、单细胞ATAC-SEQ和微 规模化芯片分析完全表征肿瘤浸润性Treg细胞的转录特征，过渡 (4-1BB+)Treg细胞和TfR细胞。Treg-TO不同发育阶段增强子的研究 TFR的差异化可能会为指导这一差异化步骤的TF提供至关重要的见解。这些 分析还将确定对提高TfR细胞抑制能力至关重要的基因和Tf 至于它们的维持或分化。耗尽Treg细胞的策略或使用 增强抗肿瘤免疫的目的正在被广泛研究。然而，至关重要的是，其中大多数 这些方法是基于抗体(即针对Treg细胞耗竭而优化的ADCC；即抗CTLA-4)，它具有 体内有很长的半衰期，因此增加了导致irAEs的可能性。相反，我们的数据表明 不同剂量的磷脂酰肌醇3-激酶δ(PI3Kδ)抑制剂可能提供靶向转铁蛋白受体的途径 更具体地说，细胞。我们认为，PI3Kδ是一种新的、有吸引力的固体免疫治疗靶点。 肿瘤。在目标2和目标3中，我们将评估PI3Kd抑制剂的替代剂量方案是否可以 用于有效和安全地开发PI3Kδ抑制剂在实体肿瘤和 TFR细胞的短暂耗尽或抑制是否足以限制免疫抑制的环境 抗肿瘤作用，从而促进抗肿瘤免疫，而不会产生毒性。