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

• 成果类型: Article
• 署名作者: Elewaut, Anais; Estivill, Guillem; Bayerl, Felix; Castillon, Leticia; Novatchkova, Maria; Pottendorfer, Elisabeth; Hoffmann-Haas, Lisa; Schonlein, 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; Munoz i Ordono, Miquel; Wiesner, Thomas; Zuber, Johannes; Jonsson, Goran; Bottcher, Jan P.; Vanharanta, Sakari; Obenauf, Anna C.
• 署名单位: Vienna Biocenter (VBC); Research Institute of Molecular Pathology (IMP); Vienna Biocenter (VBC); University of Vienna; Medical University of Vienna; Technical University of Munich; University of Helsinki; Lund University; University of Lausanne; Ludwig Institute for Cancer Research; University of Lausanne; Centre Hospitalier Universitaire Vaudois (CHUV); University of Lausanne; University of Sydney; Melanoma Institute Australia; University of Sydney; University of Sydney; Medical University of Vienna; University of Helsinki
• 刊物名称: Nature
• ISSN/ISSBN: 0028-1473
• DOI: 10.1038/s41586-024-08257-4
• 发表日期: 2025-01-16
• 关键词: dendritic cells; resistance; cdc1; activation; responses; melanoma; PROGRAMS; reveals; evasion; network

摘要

The tumour microenvironment is programmed by cancer cells and substantially influences anti-tumour immune responses1,2. Within the tumour microenvironment, CD8+ T cells undergo full effector differentiation and acquire cytotoxic anti-tumour functions in specialized niches3-7. Although interactions with type 1 conventional dendritic cells have been implicated in this process3-5,8-10, the underlying cellular players and molecular mechanisms remain incompletely understood. Here we show that inflammatory monocytes can adopt a pivotal role in intratumoral T cell stimulation. These cells express Cxcl9, Cxcl10 and Il15, but in contrast to type 1 conventional dendritic cells, which cross-present antigens, inflammatory monocytes obtain and present peptide-major histocompatibility complex class I complexes from tumour cells through 'cross-dressing'. Hyperactivation of MAPK signalling in cancer cells hampers this process by coordinately blunting the production of type I interferon (IFN-I) cytokines and inducing the secretion of prostaglandin E2 (PGE2), which impairs the inflammatory monocyte state and intratumoral T cell stimulation. Enhancing IFN-I cytokine production and blocking PGE2 secretion restores this process and re-sensitizes tumours to T cell-mediated immunity. Together, our work uncovers a central role of inflammatory monocytes in intratumoral T cell stimulation, elucidates how oncogenic signalling disrupts T cell responses through counter-regulation of PGE2 and IFN-I, and proposes rational combination therapies to enhance immunotherapies. Inflammatory monocytes are identified as important players in T cell restimulation in the tumour microenvironment.