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

Anais Elewaut, Guillem Estivill, Felix Bayerl, Leticia Castillon, Maria Novatchkova, Elisabeth Pottendorfer, Lisa Hoffmann-Haas, Martin Schönlein, Trung Viet Nguyen, Martin Lauss, Francesco Andreatta, Milica Vulin, Izabela Krecioch, Jonas Bayerl, Anna-Marie Pedde, Naomi Fabre, Felix Holstein, Shona M. Cronin, Sarah Rieser, Denarda Dangaj Laniti, David Barras, George Coukos, Camelia Quek, Xinyu Bai, Miquel Muñoz i Ordoño, Thomas Wiesner, Johannes Zuber, Göran Jönsson, Jan P. Böttcher, Sakari Vanharanta and Anna C. Obenauf ()
Additional contact information
Anais Elewaut: Vienna BioCenter (VBC)
Guillem Estivill: Vienna BioCenter (VBC)
Felix Bayerl: Technical University of Munich (TUM)
Leticia Castillon: University of Helsinki
Maria Novatchkova: Vienna BioCenter (VBC)
Elisabeth Pottendorfer: Vienna BioCenter (VBC)
Lisa Hoffmann-Haas: Vienna BioCenter (VBC)
Martin Schönlein: Vienna BioCenter (VBC)
Trung Viet Nguyen: Vienna BioCenter (VBC)
Martin Lauss: Lund University
Francesco Andreatta: Vienna BioCenter (VBC)
Milica Vulin: Vienna BioCenter (VBC)
Izabela Krecioch: Vienna BioCenter (VBC)
Jonas Bayerl: Vienna BioCenter (VBC)
Anna-Marie Pedde: Technical University of Munich (TUM)
Naomi Fabre: Vienna BioCenter (VBC)
Felix Holstein: Vienna BioCenter (VBC)
Shona M. Cronin: Vienna BioCenter (VBC)
Sarah Rieser: Vienna BioCenter (VBC)
Denarda Dangaj Laniti: University of Lausanne (UNIL)
David Barras: University of Lausanne (UNIL)
George Coukos: University of Lausanne (UNIL)
Camelia Quek: The University of Sydney
Xinyu Bai: The University of Sydney
Miquel Muñoz i Ordoño: Vienna BioCenter (VBC)
Thomas Wiesner: Medical University of Vienna
Johannes Zuber: Vienna BioCenter (VBC)
Göran Jönsson: Lund University
Jan P. Böttcher: Technical University of Munich (TUM)
Sakari Vanharanta: University of Helsinki
Anna C. Obenauf: Vienna BioCenter (VBC)

Nature, 2025, vol. 637, issue 8046, 716-725

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41586-024-08257-4

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