Function of IL35+ B cells in pancreatic cancer

胰腺导管腺癌(Pdac)是出了名的对治疗的抵抗，并且有一个令人沮丧的五年存活率。 费率。PDAC的发展伴随着间质反应和免疫监视的变化 计划，这些计划现在被认为是PDAC肿瘤演变的主要驱动力，并有助于治疗 抵抗。我们最近证实，表达免疫调节细胞因子IL35的B细胞是 在小鼠模型中支持PDAC的生长所必需的。这项提案的首要目标是 阐明IL-35在B细胞中表达促肿瘤作用的机制，并探讨IL-35在B细胞中的表达 靶向IL35通路作为加强免疫治疗的新手段的翻译潜力 疾病。在目标1中，我们将确定IL35表达的B细胞在建立免疫抑制中的重要作用 采用B细胞特异性IL35敲除和嵌合骨髓重建的PDAC微环境。在……里面 目的2，我们将阐明B细胞受体(BCR)和CD40信号在诱导IL-35表达中的作用。 肿瘤反应性B细胞。为了完成这项任务，我们将使用或分析表达固定BCR的鼠标模型 没有抗原暴露，以及B细胞中缺乏CD40信号的小鼠模型。我们还将表演 原代B细胞和B细胞系的信号通路分析。在目标3中，我们将评估翻译潜力 以PDAC中的致病B细胞为靶点。具体来说，我们将对基因进行量化、功能表征和研究 白介素35B细胞亚群在PDAC患者血液和手术切除组织中的表达特征 此外，我们将评估联合免疫检查点阻断的抗IL35治疗是一种新的治疗方法。 同基因小鼠PDAC模型的治疗策略。我们提议的研究将提供一个理解 对于PDAC中B细胞介导功能的一个以前未描述的方面，使用最先进的PDAC小鼠 模型测试阻断TME免疫抑制通路以增强T细胞影响的策略 重振治疗，并提供对人PDAC中IL35B细胞的定量和定性评估。 这个项目将扩大我们对IL35如何塑造免疫抑制肿瘤微环境的理解 并可能为胰腺癌B细胞导向免疫治疗策略的优化设计提供参考。

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.