Modulation of the human pancreatic microenvironment by combined cytokine and immune checkpoint blockade

通过联合细胞因子和免疫检查点阻断来调节人胰腺微环境

• 批准号: 10544304
• 负责人: Bassel El-Rayes
• 金额: $ 17.93万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10544304
• 关键词: Address; Applications Grants; Biology; Biopsy; Biopsy Specimen; Blocking Antibodies; Blood; Blood specimen; CCR; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cells; Circulation; Clinical; Clinical Research; Clinical Trials; Combined Modality Therapy; Complement; Correlative Study; Coupled; Cytometry; Data; Data Set; Dendritic Cells; Disease; Equilibrium; Fibroblasts; Functional disorder; Future; Goals; Hormone secretion; Human; Immune; Immunity; Immunofluorescence Immunologic; Immunologic Factors; Immunologic Markers; Immunologics; Immunotherapy; Inflammatory; Interleukin-6; Maintenance; Malignant Neoplasms; Measures; Mediator; Modeling; Mus; Myelogenous; Myeloid Cells; Myeloid-derived suppressor cells; Myristica fragrans; Neoplasm Metastasis; PD-1 blockade; Pancreas; Pancreatic Ductal Adenocarcinoma; Patients; Phase Ib/II Clinical Trial; Phenotype; Population; Pre-Clinical Model; Proteins; Publications; Publishing; Regimen; Reporting; Research; Resistance; Role; Sampling; Source; Specimen; T cell infiltration; T-Lymphocyte; Testing; Tissues; Translating; Treatment outcome; Tumor Promotion; Work; anti-PD-1; anti-tumor immune response; cytokine; effector T cell; first-in-human; immune checkpoint; immune checkpoint blockade; improved; in vivo; innovation; mouse model; novel; pancreatic ductal adenocarcinoma model; pancreatic neoplasm; pancreatic stellate cell; peripheral blood; pre-clinical; preclinical study; programmed cell death ligand 1; programmed cell death protein 1; programs; residence; response; restraint; stem; translational approach; tumor; tumor microenvironment

PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDAC) harbors significant barriers restraining immunity. One notable factor is the fibrotic stroma, driven by cancer associated fibroblast (CAF) subsets. Another is the myeloid-skewed immune composition of TIL in PDAC tumors, which lack robust effector T cell infiltration. We postulate that interleukin-6 (IL-6) is a critical factor that promotes inflammatory CAF, enables suppressive myeloid cell residence, along with T cell dysfunction in PDAC. Using innovative translational approaches and patient specimens, we will address relationships between IL-6, CAF and the balance of myeloid and T cells in metastatic human PDAC. Studies in pre-clinical models support a role for these factors in both primary and metastatic PDAC tumors, and our work will invigorate further discovery by studying tumor and blood samples from patients where IL-6, a key cytokine mediator, is blocked along with the PD-1 immune checkpoint. This data will enhance our understanding of how CAF interact with cytokines and immune cells in metastatic foci. This proposal addresses the scientific premise that IL-6 acting directly on CAF and immune cells are key mechanisms for maintaining an immunologically “cold” tumor microenvironment (TME) in metastatic PDAC and contributes to immunotherapy resistance. We will test our overall hypothesis that IL-6 restrains immunity against PDAC, through its effects on CAF and immune cells, and that targeting it reprograms the TME to enhance efficacy of immunotherapy. Prior publications from our group have demonstrated a role for IL-6 in PDAC and shown in mouse models how targeting it can improve efficacy of immune checkpoint blockade. These extensive efforts have culminated in this proposal, which will translate into patients a first-in-human trial of IL-6 and PD-1 blockade in PDAC. This trial provides a needed study of how IL-6 and CAF are related to balance of immune cells in metastatic tumors. This proposal represents an important opportunity to uncover connections between CAF, immune cells and IL-6 in metastatic disease in patients. We will conduct two specific aims. First, we will determine how dual blockade of IL-6 and PD-1 orchestrates the balance of CAF populations in tumors from metastatic PDAC patients. In this aim, we will generate foundational data using human samples from paired pre- and on-treatment biopsies of PDAC metastases from the clinical trial. Composition of CAF will be measured via multiplex immunofluorescence (IF) to uncover how therapy modulates fibroblast subsets in metastatic PDAC. Second, we will determine how targeting IL-6 and PD-1 influences the balance of T and myeloid cells in metastatic PDAC tumors and systemic circulation. We will utilize single cell mass cytometry approaches on paired biopsies and blood to study immune phenotype reprogramming in metastases and systemic longitudinal changes during treatment and relationship to clinical response. This study will impact our understanding of how immunotherapy can be improved and provide a rich dataset related to both stroma and immune markers in metastatic PDAC to facilitate subsequent treatment opportunities.

项目摘要 胰腺导管腺癌（PDAC）具有明显的免疫抑制屏障。一个值得注意的因素是 是由癌症相关成纤维细胞（CAF）亚群驱动的纤维化基质。另一个是骨髓偏侧 图2示出了PDAC肿瘤中TIL的免疫组成，其缺乏稳健的效应T细胞浸润。我们推测 白细胞介素-6（IL-6）是促进炎性CAF关键因子， 居住，沿着PDAC中的T细胞功能障碍。使用创新的翻译方法和患者 我们将讨论IL-6、CAF与转移性淋巴瘤中髓系和T细胞平衡之间的关系。 人PDAC。在临床前模型中的研究支持这些因素在原发性和转移性肿瘤中的作用。 PDAC肿瘤，我们的工作将通过研究患者的肿瘤和血液样本来激发进一步的发现 其中IL-6（一种关键的细胞因子介质）与PD-1免疫检查点一起被沿着。这些数据将增强 我们对CAF如何与转移灶中的细胞因子和免疫细胞相互作用的理解。这项建议 提出了一个科学前提，即IL-6直接作用于CAF和免疫细胞是 在转移性PDAC中维持免疫学“冷”肿瘤微环境（TME），并有助于 免疫治疗抵抗。我们将检验我们的总体假设，即IL-6抑制针对PDAC的免疫， 通过其对CAF和免疫细胞的作用，靶向它重新编程TME， 免疫治疗的功效。我们小组先前的出版物已经证明了IL-6在PDAC中的作用， 在小鼠模型中显示了靶向它如何提高免疫检查点阻断的功效。这些广泛 这项提案的提出使研究工作达到了高潮，它将使IL-6和PD-1的首次人体试验转化为患者试验 封锁PDAC。本试验为IL-6和CAF与免疫平衡的关系提供了必要的研究。 转移性肿瘤中的细胞。这一提议是一个重要的机会，可以揭示 CAF、免疫细胞和IL-6在转移性疾病患者中的作用。我们将实现两个具体目标。一是 确定IL-6和PD-1的双重阻断如何协调肿瘤中CAF群体的平衡， 转移性PDAC患者。在这个目标中，我们将使用来自配对的预处理的人类样本生成基础数据， 和来自临床试验的PDAC转移的治疗中活检。CAF的成分将通过以下方式测量 多重免疫荧光（IF）来揭示治疗如何调节转移性PDAC中的成纤维细胞亚群。 其次，我们将确定靶向IL-6和PD-1如何影响T细胞和髓系细胞的平衡， 转移性PDAC肿瘤和体循环。我们将利用单细胞质量细胞术方法进行 配对活检和血液，以研究转移瘤中的免疫表型重编程和全身纵向 治疗期间的变化以及与临床应答的关系。这项研究将影响我们对 免疫治疗可以得到改善，并提供与基质和免疫标记物相关的丰富数据集， 转移性PDAC以促进后续治疗机会。