Cancer cells impair monocyte-mediated T cell stimulation to evade immunity
The tumour microenvironment is programmed by cancer cells and substantially influences anti-tumour immune responses<sup>1,2</sup>. Within the tumour microenvironment, CD8<sup>+</sup> T cells undergo full effector differentiation and acquire cytotoxic anti-tumour functions in specialized niches<sup>3-7</sup>. Although interactions with type 1 conventional dendritic cells have been implicated in this process<sup>3-5,8-10</sup>, 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 E<sub>2</sub> (PGE<sub>2</sub>), which impairs the inflammatory monocyte state and intratumoral T cell stimulation. Enhancing IFN-I cytokine production and blocking PGE<sub>2</sub> 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 PGE<sub>2</sub> and IFN-I, and proposes rational combination therapies to enhance immunotherapies.
Authors
- Thomas Wiesner (ORCID: https://orcid.org/0000-0001-5877-2992)
- Naomi Fabre (ORCID: https://orcid.org/0000-0001-9316-3869)
- Milica Vulin (ORCID: https://orcid.org/0000-0002-7686-5102)
- Leticia Castillon (ORCID: https://orcid.org/0009-0007-2110-3825)
- George Coukos (ORCID: https://orcid.org/0000-0001-8813-7367)
- Anais Elewaut
- Maria Novatchkova (ORCID: https://orcid.org/0000-0002-8462-7171)
- Sarah Rieser (ORCID: https://orcid.org/0000-0001-5374-1871)
- Martin Lauss
- Xinyu Bai (ORCID: https://orcid.org/0000-0003-4212-1938)
- Jan P. Böttcher (ORCID: https://orcid.org/0000-0002-8163-8107)
- Izabela Kręcioch (ORCID: https://orcid.org/0000-0002-3629-8123)
- Felix Holstein (ORCID: https://orcid.org/0000-0002-3729-9857)
- Francesco Andreatta (ORCID: https://orcid.org/0000-0003-2749-9115)
- Guillem Estivill (ORCID: https://orcid.org/0000-0002-8088-3098)
- Camelia Quek (ORCID: https://orcid.org/0000-0002-1244-961X)
- Denarda Dangaj Laniti (ORCID: https://orcid.org/0000-0002-5659-6427)
- Shona M. Cronin (ORCID: https://orcid.org/0000-0003-3602-7160)
- Martin Schönlein (ORCID: https://orcid.org/0000-0002-1010-0975)
- Sakari Vanharanta (ORCID: https://orcid.org/0000-0001-5619-7963)
- Anna‐Marie Pedde
- Anna C. Obenauf (ORCID: https://orcid.org/0000-0002-9556-5914)
- Felix Bayerl (ORCID: https://orcid.org/0000-0002-4737-1808)
- Göran Jönsson (ORCID: https://orcid.org/0000-0001-6865-0147)
- David Barras (ORCID: https://orcid.org/0000-0001-8985-4704)
- Jonas Bayerl (ORCID: https://orcid.org/0000-0001-6270-2823)
- Johannes Zuber (ORCID: https://orcid.org/0000-0001-8810-6835)
- Elisabeth Pottendorfer (ORCID: https://orcid.org/0009-0004-5864-5546)
- T Nguyen (ORCID: https://orcid.org/0009-0000-1574-9610)
- Miquel Muñoz i Ordoño
- Lisa Hoffmann-Haas
Institutions
- The University of Sydney (AU)
- University of Helsinki (FI)
- Lund University (SE)
- Research Institute of Molecular Pathology (AT)
- Ludwig Cancer Research (CH)
- Melanoma Institute Australia (AU)
- Vienna Biocenter (AT)
- Technical University of Munich (DE)
- Medical University of Vienna (AT)
- University of Lausanne (CH)
Publication Details
- Journal
- Nature
- Published
- 2024-11-27
- DOI
- https://doi.org/10.1038/s41586-024-08257-4
- Citations
- 99
- Primary Topic
- Immunotherapy and Immune Responses
- Type
- article
- Field-Weighted Citation Impact
- 23.81