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Role of hypoxia in CD8+ T cell exclusion and suppression in pancreatic cancer

缺氧在胰腺癌 CD8 T 细胞排除和抑制中的作用

基本信息

批准号：
10677371
负责人：
Ashley Mello
金额：
$ 4.04万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10677371
关键词：
Antitumor Response Area Beds CD8-Positive T-Lymphocytes CD8B1 gene CXCL9 gene Cancer Etiology Cell physiology Cells Cessation of life Chemotactic Factors Clinical Data Data Set Desmoplastic Development Disease Exclusion Exposure to Fibroblasts Glioblastoma Goals Human Hypoxia Immune Evasion Immunosuppression Immunotherapeutic agent Immunotherapy In Vitro Infiltration Inflammatory LIF gene Macrophage Malignant Neoplasms Malignant neoplasm of pancreas Measures Mediating Mus Nutrient Organoids Oxygen Pancreatic Ductal Adenocarcinoma Patient-Focused Outcomes Play Population Proliferating Property Reaction Regulation Repression Resistance Role Stromal Cells Survival Rate T cell infiltration T-Cell Activation T-Lymphocyte Testing Tissues United States Vascularization cancer cell checkpoint therapy cytokine cytotoxic cytotoxic CD8 T cells design exhaustion experience insight negative affect neoplastic cell neutralizing antibody normoxia novel therapeutic intervention pancreatic cancer cells pancreatic neoplasm prevent recruit response single-cell RNA sequencing targeted treatment tumor tumor hypoxia tumor microenvironment tumor progression tumor-immune system interactions tumorigenesis

项目摘要

PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy characterized by poor response to all existing therapies. Although immunotherapy has shown great promise against multiple deadly cancers, single-agent checkpoint immunotherapy has been largely ineffective in PDAC. This lack of response is in part attributed to its extensive inflammatory, desmoplastic stromal reaction and hypoxic microenvironment. Although tumor hypoxia induces adaptive changes in both cancer cells and the surrounding stroma, most studies on the role of hypoxia in tumorigenesis have focused on cancer cell-intrinsic properties. The impact of hypoxia on stromal cells themselves and their interactions with cancer cells has remained largely unknown. The major cell populations found within the PDAC stroma—macrophages and fibroblasts—are known to be large producers of immunosuppressive factors, some of which can negatively affect cytotoxic CD8+ T cell activity in tumors. CD8+ T cells play an essential role in the anti-tumor response and the efficacy of immunnotherapies relies on the amount of CD8+ T cell infiltration within the tumor bed. Based on our preliminary observation that macrophages and inflammatory fibroblasts are enriched in hypoxic tumor regions while T cells are excluded from hypoxic areas in PDAC, I hypothesize that hypoxia suppresses infiltration and activation of CD8+ T cells by modulating their interactions with macrophages and fibroblasts. In Specific Aim 1, I will determine whether macrophages are critical for hypoxia-mediated CD8+ T cell exclusion and suppression by treating CD8+ T cells with conditioned media derived from macrophage cultures under hypoxia and depleting macrophages in syngeneic orthotopic PDAC tumors. In Specific Aim 2, I will determine how fibroblasts regulate CD8+ T cell recruitment and function in hypoxic tumor regions by blocking a factor secreted from fibroblasts in syngeneic orthotopic PDAC tumors, injecting a hypoxia probe into mice, and assessing CD8+ T cell infiltration and activation in hypoxic and normoxic tumor regions. The results of my studies will further the field’s understanding of how hypoxia drives an immunosuppressive microenvironment via the crosstalk between CD8+ T cells, macrophages, and fibroblasts, and thus aid in the development of effective immunotherapeutic strategies.

项目摘要胰腺导管腺癌（PDAC）是一种致命的恶性肿瘤，其特征是对所有现有的化疗药物反应不良。治疗尽管免疫疗法对多种致命癌症表现出巨大的希望，检查点免疫疗法在PDAC中基本上无效。这种缺乏反应的部分原因是，广泛的炎症、促结缔组织增生的基质反应和缺氧的微环境。虽然肿瘤缺氧诱导癌细胞和周围基质的适应性变化，大多数关于缺氧作用的研究在肿瘤发生中的研究集中在癌细胞的内在特性上。缺氧对基质细胞的影响它们本身及其与癌细胞的相互作用在很大程度上仍然未知。主要细胞群在PDAC基质中发现的巨噬细胞和成纤维细胞已知是PDAC的大生产者。免疫抑制因子，其中一些可以负面影响肿瘤中的细胞毒性CD8+ T细胞活性。CD8+ T细胞在抗肿瘤应答中起重要作用，免疫疗法的功效依赖于T细胞的免疫应答。肿瘤床内的CD8+ T细胞浸润量。根据我们的初步观察，并且炎性成纤维细胞在缺氧肿瘤区域中富集，而T细胞被排除在缺氧区域之外在PDAC中，我假设缺氧通过调节CD8+ T细胞的浸润和活化来抑制它们，与巨噬细胞和成纤维细胞的相互作用。在具体目标1中，我将确定巨噬细胞是否对于通过用条件化的抗CD8 + T细胞治疗缺氧介导的CD8 + T细胞排斥和抑制至关重要培养基来源于缺氧条件下的巨噬细胞培养物，并消耗同系原位 PDAC肿瘤在具体目标2中，我将确定成纤维细胞如何调节CD8+ T细胞的募集和功能通过阻断同源原位PDAC肿瘤中成纤维细胞分泌的因子，将缺氧探针注射到小鼠体内，并评估缺氧和常氧中CD 8 + T细胞的浸润和活化肿瘤区域。我的研究结果将进一步了解该领域的缺氧如何驱动一个通过CD8+ T细胞、巨噬细胞和成纤维细胞之间的相互作用，从而有助于发展有效的免疫策略。