The role of plasma cell activation and metabolism in colorectal carcinogenesis and metastasis

浆细胞活化和代谢在结直肠癌发生和转移中的作用

• 批准号: 428413316
• 负责人: Professor Dr. Stefan Fichtner-Feigl
• 金额: --
• 依托单位: Klinik für Allgemein- und Viszeralchirurgie
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/428413316?language=en
• 关键词: role; plasma; cell; activation; metabolism

In the last decade the focus for cancer treatment has moved away from drugs that target the tumor broadly or just the tumor cells themselves (like chemotherapy and radiation) towards immunotherapies that affect distinct cells and cell interaction in the tumor microenvironment. Although the recent advancement of immunotherapy was encouraging, and many patients have achieved significant benefits, the vast majority of patients still do not respond to immunotherapy, partly due to the complexity and diversity of the tumor microenvironment. In colorectal cancer (CRC) research largely concentrates on the role of T cells and antigen presenting cells in the tumor microenvironment. However, CRCs are infiltrated by diverse B cell subsets, but their roles in colorectal carcinogenesis are largely unknown. In the last funding period, we could show that human colorectal carcinoma – particularly at the invasive margin – are enriched in infiltrating B cells consisting of naïve, memory B cells and plasma cells. Thus distinct B cell subsets present in the tumor microenvironment influence the prognosis of CRC patients either positively or negatively. In mechanistic analysis we have shown that B cells set the stage for anti-tumoral immune responses in the tumor microenvironment of colorectal cancer via induction of innate lymphoid cells (ILC) as well as cytotoxic T and NK cell responses, while at the same time dampening cellular immunosuppressive effects. Specifically, our results lead to the hypothesis that these anti-tumoral functions are induced by tumor-infiltrating bacteria engaging pattern recognition receptor (PRR) signaling in plasma cells with consecutive inflammasome activation. Therefore, we will analyze PRR signaling in plasma cells in the tumor microenvironment of colorectal cancer and its impact on anti-tumoral immune responses. These anti-tumoral effects are potentially built on metabolic reprogramming of tumor-infiltrating plasma cells, as we could demonstrate altered metabolic profiles of human tumor-infiltrating B cells.

在过去的十年中，癌症治疗的重点已转移到广泛针对肿瘤的药物，或者仅仅是肿瘤细胞本身（例如化学疗法和放射线）朝向影响肿瘤微环境中不同细胞和细胞相互作用的免疫疗法。尽管最近的免疫疗法进步令人鼓舞，许多患者已经获得了显着的好处，但绝大多数患者仍然对免疫疗法没有反应，部分原因是肿瘤微环境的复杂性和多样性。在结直肠癌（CRC）中，研究主要集中于T细胞和抗原呈现细胞在肿瘤微环境中的作用。但是，CRC被潜水B细胞子集渗透，但是它们在结直肠癌中的作用在很大程度上尚不清楚。在最后一个资金期间，我们可以证明人的结直肠癌（尤其是在侵入性边缘时）富含由幼稚，记忆B细胞和浆细胞组成的浸润B细胞。肿瘤微环境中存在的不同B细胞子集对CRC患者的预后产生了积极或负面影响。在机械分析中，我们已经表明，B细胞为结直肠癌肿瘤微环境的抗肿瘤免疫反应树立了阶段，这是通过诱导先天淋巴样细胞（ILC）以及细胞毒性T和NK细胞反应的阶段，同一时间抑制了细胞免疫效应，我们的作用是不足的。肿瘤浸润细菌吸引了模式识别受体（PRR）信号传导，并具有连续炎症体激活的血浆细胞。因此，我们将分析大肠癌肿瘤微环境中浆细胞中的PRR信号传导及其对抗肿瘤免疫调查的影响。这些抗肿瘤作用可能建立在肿瘤浸润浆细胞的代谢重编程上，因为我们可以证明人类肿瘤浸润B细胞的代谢谱改变。