The influence of B cells on the therapeutic success of immunotherapy in patients with head and neck cancer

B细胞对头颈癌患者免疫治疗成功的影响

• 批准号: 504016957
• 负责人: Professorin Dr. Cornelia Brunner
• 金额: --
• 依托单位: Universitätsklinik für Hals-, Nasen- und Ohrenheilkunde
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/504016957?language=en
• 关键词: influence; cells; therapeutic; success; immunotherapy

The role of tumor-infiltrating B cells in solid tumors has long been underestimated. Only in the last few years has it become clear that the presence of B cells is often associated with a good prognosis in a variety of solid cancers such as head and neck cancer (HNC). On the other hand, B cells are also assigned a tumor-promoting role, which is supported by several murine tumor models. For further investigations it is therefore necessary to further subdivide the B-cell population into immunocompetent effector B-cells and immunosuppressive regulatory B-cells.The possibilities of immunotherapy with checkpoint inhibitors (CPI), such as PD1 antibodies, have also led to an increase in survival in patients with KHT. Since patients with tumors who do not express the PD-L1 ligand, also benefit from this therapy, the exact mechanism of action of the PD-1 antibodies has not yet been clarified. Likewise, there are no reliable prognostic markers for this therapy.In the context of the present application, we are investigating how different B-cell populations can influence therapy with CPI. The first section examines how CPI can strengthen the immune system and in particular B-cell function in vitro. This is done using blood and tumor samples from patients with HNC or from healthy control donors. Mass spectrometry, UMAP flow cytometry and experiments with tumor organoids are used here.The second section focuses on the influence of CPI on the immune system in an established, orthotopic murine tumor model. In this model, CPI are combined with other antibodies (anti-CD20, anti-CD73) or B-cell-specific proteins are deleted by knockout methods.The third section examines how the function of B cells can be modified with the help of tumor-derived exosomes. These studies are carried out both in vivo and in vitro. The exosomes are isolated using mini-size exclusion chromatography and visualized by nanoparticle tracking.The fourth section correlates the clinical data of our tumor patients treated with CPI with the occurrence of B-cell populations and tertiary lymphoid structures in the tumor. Existing tumor microarrays allow the investigation of a large number of tumor samples. Serum samples from patients are examined for antigen patterns using multiplex serology.The aim of the application is to improve oncological therapy by manipulating B cells in the tumor microenvironment of patients with HNC. These results can be transferred to other types of tumors in the further course. The areas of activity of the two applicants, on the one hand in the clinic and on the other hand in the research laboratory, are complementary and thus promote the rapid and successful implementation of the suggested experiments.

长期以来低估了肿瘤浸润B细胞在实体瘤中的作用。仅在过去的几年中，B细胞的存在通常与各种固体癌症（例如头颈癌（HNC））的预后良好有关。另一方面，B细胞还分配了促进肿瘤的作用，该作用得到了几种鼠肿瘤模型的支持。因此，为了进一步研究，有必要将B细胞种群进一步细分为免疫功能的效应B细胞和免疫抑制性调节B细胞。通过检查点抑制剂（CPI）的免疫疗法的可能性，例如PD1抗体，也导致KHT患者的生存率增加。由于未表达PD-L1配体的肿瘤患者也从这种疗法中受益，因此尚未阐明PD-1抗体的确切作用机理。同样，这种疗法也没有可靠的预后标记。在本应用的背景下，我们正在研究不同的B细胞种群如何影响CPI治疗。第一部分研究了CPI如何在体外加强免疫系统，尤其是B细胞功能。这是使用来自HNC患者或健康对照供体的患者的血液和肿瘤样品完成的。这里使用质谱，UMAP流式细胞术和肿瘤器官实验。第二部分侧重于CPI对已建立的原位鼠肿瘤模型中CPI对免疫系统的影响。在该模型中，CPI与其他抗体（抗CD20，抗CD73）或B细胞特异性蛋白结合使用，通过敲除方法删除。第三部分研究如何在肿瘤衍生的外泌体的帮助下如何修饰B细胞的功能。这些研究均在体内和体外进行。外泌体是使用微型排除色谱分离的，并通过纳米颗粒跟踪可视化。第四部分将用CPI治疗的肿瘤患者的临床数据与肿瘤中的B细胞群体和第三级淋巴样结构相关联。现有的肿瘤微阵列允许研究大量肿瘤样品。使用多重血清学检查了患者的血清样品的抗原模式。该应用的目的是通过操纵HNC患者肿瘤微环境中的B细胞来改善肿瘤疗法。这些结果可以在进一步的过程中将其转移到其他类型的肿瘤中。两者的活动领域，一方面是诊所中的一方面，另一方面是研究实验室的互补，因此促进了建议的实验的快速和成功实施。