Interplay between inflammation and autophagy in dendritic cells during cancer immune evasion

癌症免疫逃避过程中树突状细胞炎症与自噬之间的相互作用

• 批准号: EP/X027473/1
• 负责人: Ghita Ghislat
• 金额: $ 26万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FX027473%2F1
• 关键词: Interplay; between; inflammation; autophagy; dendritic

Cancer inflammation can favour efficient tumour rejection or development i.e via evasion from immune surveillance. Despite recent advances in understanding the immuno-regulatory and anti-inflammatory mechanisms of cancer immune evasion, it is important to elucidate the pro-inflammatory machinery behind this process towards combinatorial therapy against inflammatory cancer. Dendritic cells (DCs) are central actors for anti-tumour immune responses. They stand out in the uptake of proteins from tumour cells, followed by lysosomal processing and presentation of tumour-associated antigens to lymphocytes to prime their activity against tumours. Antigen-presentation in DCs was suggested to be regulated by autophagy, a lysosomal pathway degrading intracellular cargos for their re-use to maintain cellular homeostasis and functions. However, autophagy role in DC function within inflammatory tumour microenvironment (TME) in vivo remains largely unexplored. How autophagy in DCs affects their function against cancer, and how inflammatory TME affects autophagy in DCs remain 2 sine-qua-non questions with no clear answer so far. Whence, I will endeavour to address these questions in well-established tumour models by joining my strong background in autophagy and know-how in DC biology with the expertise of the host lab on lymphocytes in tumour inflammation. Promising observations from preliminary data I generated suggest that inflammatory tumours restrain autophagy in DCs to evade immune surveillance, which prompted me to build the hypothesis behind this project. I intend to test this hypothesis by employing state-of-the-art murine melanoma models mimicking inflammatory "hot" and non-inflammatory "cold" tumours engrafted in bi-transgenic mice bearing autophagy-deficient DCs. The expected outcomes of this project will tackle the central issue of inflammatory cancer immune evasion, whose cause and mechanism are still obscure despite their importance for immunotherapies efficiency.

癌症炎症有利于有效的肿瘤排斥或发展，即通过逃避免疫监视。尽管最近在了解癌症免疫逃避的免疫调节和抗炎机制方面取得了进展，但阐明这一过程背后的促炎机制对炎症性癌症的联合治疗非常重要。树突状细胞（dc）是抗肿瘤免疫反应的核心参与者。它们在从肿瘤细胞中摄取蛋白质，随后溶酶体加工并将肿瘤相关抗原呈递给淋巴细胞以启动其抗肿瘤活性方面表现突出。抗原在dc中的呈递被认为是由自噬调节的，自噬是一种溶酶体途径，可以降解细胞内的货物，使其重新利用以维持细胞的稳态和功能。然而，体内炎症性肿瘤微环境（TME）中自噬在DC功能中的作用仍未得到充分研究。dc中的自噬如何影响其抗癌功能，以及炎症性TME如何影响dc中的自噬，这两个问题至今没有明确的答案。因此，我将努力通过结合我在自噬和DC生物学方面的强大背景以及宿主实验室在肿瘤炎症中的淋巴细胞方面的专业知识，在成熟的肿瘤模型中解决这些问题。从我产生的初步数据中有希望的观察结果表明，炎症性肿瘤抑制dc中的自噬以逃避免疫监视，这促使我建立了这个项目背后的假设。我打算通过采用最先进的小鼠黑色素瘤模型来验证这一假设，该模型模拟了植入具有自噬缺陷dc的双转基因小鼠体内的炎性“热”和非炎性“冷”肿瘤。该项目的预期结果将解决炎症性癌症免疫逃避的核心问题，其原因和机制仍然不清楚，尽管它们对免疫治疗效率很重要。

项目成果

NKG2D Fine-Tunes the Local Inflammatory Response in Colorectal Cancer.

• DOI: 10.3390/cancers15061792
• 发表时间: 2023-03-16
• 期刊: Cancers
• 影响因子: 5.2