Function of IL35+ B cells in pancreatic cancer

众所周知，胰腺导管腺癌（PDAC）对治疗具有抵抗性，5年生存率低 率PDAC的发展伴随着基质反应和免疫监视的变化 这些项目现在被认为是PDAC肿瘤演变的主要驱动力，并有助于治疗 阻力我们最近证明，表达免疫调节细胞因子IL 35的B细胞是 这是支持PDAC在鼠模型中生长所必需的。本提案的总体目标是 阐明IL 35在B细胞中表达的促肿瘤作用的潜在机制，并研究IL 35在B细胞中的表达。 靶向IL 35通路的翻译潜力作为一种新的手段，以加强免疫治疗， 疾病在目的1中，我们将确定表达IL 35的B细胞在建立免疫抑制性T细胞中的重要作用。 使用IL 35的B细胞特异性敲除和嵌合骨髓重建在PDAC中的微环境。在 目的2，我们将阐明B细胞受体（BCR）和CD 40信号转导如何在IL 35表达诱导中发挥作用。 肿瘤反应性B细胞。为了完成这项任务，我们将分析表达固定BCR的小鼠模型， 没有抗原暴露，以及在B细胞中缺乏CD40信号传导的小鼠模型。我们还将表演 原代B细胞和B细胞系中的信号传导途径分析。在目标3中，我们将评估 靶向PDAC中的致病性B细胞。具体来说，我们将量化，功能表征和研究基因， PDAC患者血液和手术切除组织中IL 35 + B细胞亚群的表达特征。 此外，我们将评估抗IL 35治疗与免疫检查点阻断的组合作为一种新的治疗方法。 在同基因鼠PDAC模型中的治疗策略。我们提议的研究将提供一种理解 PDAC中B细胞介导的功能的一个以前未表征的方面，使用最先进的PDAC鼠 模型来测试阻断TME中免疫抑制途径的策略，以增强T细胞的影响， 重振疗法，并提供人PDAC中IL 35 + B细胞的定量和定性评估。 该项目将扩大我们对IL 35如何塑造免疫抑制肿瘤微环境的理解 并且可以为针对胰腺癌的B细胞定向免疫治疗策略的最佳设计提供信息。

Pancreatic ductal adenocarcinoma (PDAC) is notoriously resistant to therapy and has a dismal 5-year survival rate. Development of PDAC is accompanied by changes in stromal responses and immune surveillance programs, which are now recognized as major drivers of PDAC tumor evolution and contribute to therapeutic resistance. We have recently demonstrated that B cells expressing the immunomodulatory cytokine IL35 are necessary to support the growth of PDAC in murine models. The overarching goals of this proposal are to elucidate mechanisms underlying the tumor-promoting effect of IL35 expression in B cells, and to investigate the translational potential of targeting the IL35 pathway as a novel means to augment immunotherapy for this disease. In Aim 1, we will define essential role for IL35 expressing B cells in establishing an immunosuppressive microenvironment in PDAC using B cell specific knockout of IL35 and chimeric bone marrow reconstitution. In Aim 2, we will clarify how B cell receptor (BCR) and CD40 signaling contribute to induction of IL35 expression in tumor-reactive B cells. To accomplish this task, we will analyze mouse models expressing a fixed BCR with or without antigen exposure, as well as mouse models lacking CD40 signaling in B cells. We will also perform signaling pathway analysis in primary B cells and B cell lines. In Aim 3, we will assess the translational potential of targeting pathogenic B cells in PDAC. Specifically, we will quantify, functionally characterize and study gene expression signature of IL35+ B cell subset in blood and surgically resected tissues from patients with PDAC. Additionally, we will evaluate anti-IL35 therapy in combination with immune checkpoint blockade as a novel therapeutic strategy in syngeneic murine PDAC models. Our proposed research will provide an understanding of a previously uncharacterized facet of B cell-mediated function in PDAC, use state-of-the-art PDAC murine models to test strategies that block immune suppressive pathways in TME to enhance the impact of T cell- reinvigorating therapies, and provide a quantitative and qualitative assessment of IL35+ B cells in human PDAC. This project will expand our understanding of how IL35 shapes the immunosuppressive tumor microenvironment and may inform the optimal design of B cell-directed immunotherapy strategies against pancreatic cancer.