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，癌症治疗的重点已经从广泛靶向肿瘤或仅靶向肿瘤细胞本身（如化疗和放疗）的药物转移到影响肿瘤微环境中不同细胞和细胞相互作用的免疫疗法。尽管免疫治疗的最新进展令人鼓舞，许多患者已经取得了显着的益处，但绝大多数患者仍然对免疫治疗没有反应，部分原因是肿瘤微环境的复杂性和多样性。在结直肠癌（CRC）研究中，主要集中在T细胞和抗原呈递细胞在肿瘤微环境中的作用。然而，CRC被不同的B细胞亚群浸润，但它们在结直肠癌发生中的作用在很大程度上是未知的。在上一个资助期，我们可以证明人类结直肠癌-特别是在浸润边缘-富含浸润性B细胞，包括幼稚、记忆B细胞和浆细胞。因此，存在于肿瘤微环境中的不同B细胞亚群对CRC患者的预后产生积极或消极的影响。在机制分析中，我们已经表明，B细胞通过诱导先天性淋巴细胞（ILC）以及细胞毒性T和NK细胞应答，为结直肠癌的肿瘤微环境中的抗肿瘤免疫应答奠定基础，同时抑制细胞免疫抑制作用。具体地说，我们的结果导致了这样的假设，即这些抗肿瘤功能是由肿瘤浸润性细菌诱导的，这些细菌在浆细胞中参与模式识别受体（PRR）信号传导，并伴有连续的炎性小体激活。因此，我们将分析结直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应答的影响。这些抗肿瘤作用可能建立在肿瘤浸润性浆细胞的代谢重编程上，因为我们可以证明人类肿瘤浸润性B细胞的代谢谱改变。