奥地利分子病理研究所Anna C. Obenauf团队发现，癌细胞通过抑制单核细胞介导的T细胞刺激来逃避免疫系统。这一研究成果于2024年11月27日在线发表在国际学术期刊《自然》上。

据介绍，肿瘤微环境由癌细胞编程，并在很大程度上影响抗肿瘤免疫反应。在肿瘤微环境中，CD8⁺ T细胞在特定的微环境中完成效应细胞分化，并获得细胞毒性抗肿瘤功能。

尽管已有研究指出，与1型常规树突状细胞的相互作用在这一过程中起着重要作用，但其背后的细胞作用者和分子机制仍未完全阐明。

研究人员发现，炎症性单核细胞可以在肿瘤内发挥重要的T细胞刺激作用。这些细胞表达Cxcl9、Cxcl10和Il15，但与1型常规树突状细胞通过交叉呈递抗原不同，炎症性单核细胞通过“交叉穿衣”从肿瘤细胞获得并呈递肽-主要组织相容性复合物I类（MHC-I）复合物。

癌细胞中MAPK信号通路的过度激活，通过协调抑制I型干扰素（IFN-I）细胞因子的产生，并诱导前列腺素E₂（PGE₂）的分泌，阻碍了这一过程，进而削弱了炎症性单核细胞的功能和肿瘤内T细胞刺激。增强IFN-I细胞因子产生并阻断PGE₂分泌能够恢复这一过程，并重新敏感肿瘤对T细胞介导的免疫反应。

综上所述，该研究揭示了炎症性单核细胞在肿瘤内T细胞刺激中的核心作用，阐明了肿瘤细胞信号如何通过对PGE2和IFN-I的相互调控破坏T细胞反应，并提出了合理的联合治疗策略以增强免疫疗法效果。

附：英文原文

Title: Cancer cells impair monocyte-mediated T cell stimulation to evade immunity

Author: Elewaut, Anais, Estivill, Guillem, Bayerl, Felix, Castillon, Leticia, Novatchkova, Maria, Pottendorfer, Elisabeth, Hoffmann-Haas, Lisa, Schnlein, Martin, Nguyen, Trung Viet, Lauss, Martin, Andreatta, Francesco, Vulin, Milica, Krecioch, Izabela, Bayerl, Jonas, Pedde, Anna-Marie, Fabre, Naomi, Holstein, Felix, Cronin, Shona M., Rieser, Sarah, Laniti, Denarda Dangaj, Barras, David, Coukos, George, Quek, Camelia, Bai, Xinyu, Muoz i Ordoo, Miquel, Wiesner, Thomas, Zuber, Johannes, Jnsson, Gran, Bttcher, Jan P., Vanharanta, Sakari, Obenauf, Anna C.

Issue&Volume: 2024-11-27

Abstract: The tumour microenvironment is programmed by cancer cells and substantially influences anti-tumour immune responses1,2. Within the tumour microenvironment, CD8+ Tcells undergo full effector differentiation and acquire cytotoxic anti-tumour functions in specialized niches3,4,5,6,7. Although interactions with type1 conventional dendritic cells have been implicated in this process3,4,5,8,9,10, the underlying cellular players and molecular mechanisms remain incompletely understood. Here we show that inflammatory monocytes can adopt a pivotal role in intratumoral Tcell stimulation. These cells express Cxcl9, Cxcl10 and Il15, but in contrast to type1 conventional dendritic cells, which cross-present antigens, inflammatory monocytes obtain and present peptide–major histocompatibility complex classI complexes from tumour cells through ‘cross-dressing’. Hyperactivation of MAPK signalling in cancer cells hampers this process by coordinately blunting the production of typeI interferon (IFN-I) cytokines and inducing the secretion of prostaglandinE2 (PGE2), which impairs the inflammatory monocyte state and intratumoral Tcell stimulation. Enhancing IFN-I cytokine production and blocking PGE2 secretion restores this process and re-sensitizes tumours to Tcell-mediated immunity. Together, our work uncovers a central role of inflammatory monocytes in intratumoral Tcell stimulation, elucidates how oncogenic signalling disrupts Tcell responses through counter-regulation of PGE2 and IFN-I, and proposes rational combination therapies to enhance immunotherapies.

DOI: 10.1038/s41586-024-08257-4

Source: https://www.nature.com/articles/s41586-024-08257-4