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

癌症炎症可以促进有效的肿瘤排斥或发展，即通过逃避免疫监视。尽管最近在理解癌症免疫逃避的免疫调节和抗炎机制方面取得了进展，但重要的是要阐明这一过程背后的促炎机制，以实现针对炎性癌症的组合治疗。树突状细胞（DC）是抗肿瘤免疫反应的中心作用者。它们从肿瘤细胞中摄取蛋白质，然后进行溶酶体加工并将肿瘤相关抗原呈递给淋巴细胞，以激发其抗肿瘤活性。DC中的抗原呈递被认为是由自噬调节的，自噬是一种降解细胞内货物的溶酶体途径，用于它们的再利用以维持细胞的稳态和功能。然而，自噬在体内炎性肿瘤微环境（TME）中DC功能中的作用在很大程度上仍未被探索。DCs中的自噬如何影响其抗癌功能，以及炎症性TME如何影响DCs中的自噬仍然是两个至今没有明确答案的问题。因此，我将努力在完善的肿瘤模型中解决这些问题，将我在DC生物学中的自噬和专业知识与宿主实验室在肿瘤炎症中的淋巴细胞方面的专业知识结合起来。从我生成的初步数据中得到的有希望的观察结果表明，炎症性肿瘤抑制了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，该模型模拟移植到携带自噬缺陷DC的双转基因小鼠中的炎性“热”和非炎性“冷”肿瘤。该项目的预期成果将解决炎症性癌症免疫逃避的核心问题，尽管其对免疫治疗效率的重要性，但其原因和机制仍不清楚。

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.