Targeting macrophages for immunotherapy in pancreatic cancer

靶向巨噬细胞用于胰腺癌免疫治疗

基本信息

批准号：
9106138
负责人：
Gregory L Beatty
金额：
$ 36.83万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9106138
关键词：
Address Advanced Malignant Neoplasm Agonist Antibodies Antigen Presentation Antigens CCL2 gene CD47 gene Cells Clinical Clinical Research Cytotoxic Chemotherapy Data Desmoplastic Development Disease Fibrosis Genetic Genetically Engineered Mouse Goals Human Immune Immune response Immune system Immunologic Monitoring Immunologics Immunosuppression Immunosuppressive Agents Immunotherapeutic agent Immunotherapy Infiltration Inflammatory Inflammatory Infiltrate Interferons Interleukin-6 Intrinsic factor Investigation Ionizing radiation Lesion Leukocytes Malignant Neoplasms Malignant neoplasm of pancreas Matrix Metalloproteinases Mediating Modality Modeling Molecular Mus Myelogenous Myeloid Cells Natural History Natural Immunity Neoplasm Metastasis Pancreas Pancreatic Ductal Adenocarcinoma Pathogenesis Patient-Focused Outcomes Patients Phagocytosis Phase Pliability Population Production Property Recruitment Activity Reporting Resistance Role STAT3 gene Shapes Signal Transduction T-Cell Activation T-Lymphocyte TNFRSF5 gene Testing Therapeutic Translating Tumor Immunity Tumor Tissue Tumor-Derived Vaccines Variant adaptive immunity cancer immunotherapy cancer therapy chemokine chemotherapy clinically relevant cytokine effective therapy human disease immune clearance improved innovation macrophage monocyte mouse model neoplastic cell novel novel therapeutics peripheral blood public health relevance resistance mechanism response therapy design therapy resistant tool tumor tumor growth tumor microenvironment tumor progression

项目摘要

DESCRIPTION (provided by applicant): Immunotherapy has emerged as a promising treatment modality for several advanced cancers. However, in pancreatic ductal adenocarcinoma (PDAC), an almost universally lethal disease with few effective treatment options, immunotherapy has remained largely ineffective. We hypothesize that the capacity of PDAC to evade immune elimination is dependent on tumor intrinsic factors which cooperate to establish a microenvironment that is immunosuppressive and supportive of tumor growth, invasion and metastasis. In support of this hypothesis, we have previously demonstrated using CD40 agonists that the immune response to PDAC in both humans and genetically engineered mice can be redirected from tumor-promoting to tumor-suppressing leading to major tumor regressions. However, not all lesions responded and unexpectedly, tumor regressions were dependent on macrophages and did not require T cells as would have been predicted from earlier studies using CD40 agonists. We have now extended these observations and have found that macrophages residing outside of the tumor microenvironment direct the infiltration of inflammatory monocytes into tumor tissue where they then mediate anti-tumor activity in response to CD40 therapy. We have also found that these same macrophages can inhibit T cell-dependent anti-tumor immune responses in PDAC. Thus, our findings demonstrate that the myeloid cell response to PDAC is pliable and can have dual and opposing roles in regulating the natural history of this deadly disease. Our ultimate goal is to devise novel therapies that redirec the myeloid cell response in PDAC from pro-tumor to anti-tumor. However, this will require an understanding of the signals that shape myeloid cell activity and their capacity to mediate anti-tumor responses and to drive productive T cell immunosurveillance. Therefore, this proposal will test the hypothesis that myeloid cells responding to PDAC can be induced with anti- tumor properties, but their capacity to mediate tumor destruction and support productive T cell immunosurveillance is regulated by tumor intrinsic factors. In Aim 1, we will define the signals that regulate the capacity of tumor infiltrating inflammatory monocytes to mediate anti-tumor activity. In Aim 2, we will then define the mechanisms by which macrophages residing outside of the tumor microenvironment regulate T cell immunosurveillance in PDAC. Together, these aims will inform the development of myeloid-directed therapies designed to align innate and adaptive immunity for cancer therapy.

描述（由申请人提供）：免疫疗法已成为多种晚期癌症的一种有前途的治疗方式，然而，对于几乎普遍致命的疾病，几乎没有有效的治疗选择，免疫疗法仍然基本上无效。 PDAC逃避免疫消除的能力取决于肿瘤内在因素，这些因素共同建立一个免疫抑制和支持肿瘤生长、侵袭和转移的微环境。根据这一假设，我们之前已经使用 CD40 激动剂证明，人类和基因工程小鼠对 PDAC 的免疫反应可以从促进肿瘤转向抑制肿瘤，从而导致肿瘤主要消退。然而，并非所有病变都有反应，而且出乎意料的是，肿瘤消退依赖于巨噬细胞，并且不需要 T 细胞，正如早期使用 CD40 激动剂的研究所预测的那样。我们现在扩展了这些观察结果，发现巨噬细胞存在于肿瘤之外。微环境引导炎症单核细胞浸润到肿瘤组织中，然后它们在 CD40 治疗中介导抗肿瘤活性，我们还发现这些相同的巨噬细胞可以抑制 PDAC 中 T 细胞依赖性抗肿瘤免疫反应。证明骨髓细胞对 PDAC 的反应是柔韧的，并且在调节这种致命疾病的自然史中可以发挥双重和相反的作用。我们的最终目标是设计新的疗法来重定向骨髓细胞反应。然而，这需要了解塑造骨髓细胞活性的信号及其介导抗肿瘤反应和驱动高效 T 细胞免疫监视的能力。骨髓细胞对 PDAC 的反应可以被诱导具有抗肿瘤特性，但它们介导肿瘤破坏和支持生产性 T 细胞免疫监视的能力受到肿瘤内在因素的调节。在目标 1 中，我们将定义调节信号。肿瘤浸润炎症单核细胞介导抗肿瘤活性的能力在目标 2 中，我们将定义肿瘤微环境之外的巨噬细胞调节 PDAC 中 T 细胞免疫监视的机制。 -旨在调整先天免疫和适应性免疫以进行癌症治疗的定向疗法。