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

Elewaut, Anais ; Estivill, Guillem ; Bayerl, Felix ; Castillon, Leticia ; Novatchkova, Maria ; Pottendorfer, Elisabeth ; Hoffmann-Haas, Lisa ; Schönlein, Martin ; Nguyen, Trung Viet and Lauss, Martin LU , et al. (2025) In Nature 637(8046). p.716-725
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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature
volume
637
issue
8046
pages
716 - 725
publisher
Nature Publishing Group
external identifiers
  • scopus:85210476344
  • pmid:39604727
ISSN
0028-0836
DOI
10.1038/s41586-024-08257-4
language
English
LU publication?
yes
id
9f49b21a-e37c-46ff-857a-4bc831d6658a
date added to LUP
2025-01-15 16:11:12
date last changed
2025-07-03 19:51:22
@article{9f49b21a-e37c-46ff-857a-4bc831d6658a,
  abstract     = {{<p>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.</p>}},
  author       = {{Elewaut, Anais and Estivill, Guillem and Bayerl, Felix and Castillon, Leticia and Novatchkova, Maria and Pottendorfer, Elisabeth and Hoffmann-Haas, Lisa and Schönlein, Martin and Nguyen, Trung Viet and Lauss, Martin and Andreatta, Francesco and Vulin, Milica and Krecioch, Izabela and Bayerl, Jonas and Pedde, Anna Marie and Fabre, Naomi and Holstein, Felix and Cronin, Shona M. and Rieser, Sarah and Laniti, Denarda Dangaj and Barras, David and Coukos, George and Quek, Camelia and Bai, Xinyu and Muñoz i Ordoño, Miquel and Wiesner, Thomas and Zuber, Johannes and Jönsson, Göran and Böttcher, Jan P. and Vanharanta, Sakari and Obenauf, Anna C.}},
  issn         = {{0028-0836}},
  language     = {{eng}},
  number       = {{8046}},
  pages        = {{716--725}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature}},
  title        = {{Cancer cells impair monocyte-mediated T cell stimulation to evade immunity}},
  url          = {{http://dx.doi.org/10.1038/s41586-024-08257-4}},
  doi          = {{10.1038/s41586-024-08257-4}},
  volume       = {{637}},
  year         = {{2025}},
}