Peritoneal resident macrophages constitute an immunosuppressive environment in peritoneal metastasized colorectal cancer
Patients with peritoneal metastasized colorectal cancer (PM-CRC) have a dismal prognosis. We hypothesized that an immunosuppressive environment in the peritoneal cavity underlies poor prognosis. We define the composition of the human peritoneal immune system (PerIS) using single-cell technologies in 18 patients with- and without PM-CRC, as well as in matched peritoneal metastases (n = 8). Here we show that the PerIS contains abundant immunosuppressive C1Q<sup>+</sup>VSIG4<sup>+</sup> and SPP1<sup>+</sup>VSIG4<sup>+</sup> peritoneal-resident macrophages (PRMs), as well as monocyte-like cavity macrophages (mono-CMs), which share features with tumor-associated macrophages, even in homeostasis. In PM-CRC, expression of immunosuppressive cytokines IL10 and VEGF increases, while simultaneously expression of antigen-presenting molecules decreases in PRMs. These intratumoral suppressive PRMs originate from the PerIS, and intraperitoneal depletion of PRMs in vivo using anti-CSF1R combined with anti-PD1 significantly reduces tumor burden and improves survival. Thus, PRMs define a metastatic site-specific immunosuppressive niche, and targeting PRMs is a promising treatment strategy for PM-CRC.
Authors
- Kristiaan Lenos (ORCID: https://orcid.org/0000-0003-1165-8732)
- Joep Grootjans (ORCID: https://orcid.org/0000-0002-2805-4831)
- Jan Verhoeff (ORCID: https://orcid.org/0000-0003-0648-0642)
- Juan J. García‐Vallejo (ORCID: https://orcid.org/0000-0001-6238-7069)
- S. Bootsma
- Onno Kranenburg (ORCID: https://orcid.org/0000-0002-2112-4390)
- Sarah Derks (ORCID: https://orcid.org/0000-0002-4547-7457)
- J Saris (ORCID: https://orcid.org/0000-0002-4430-4597)
- Manon E. Wildenberg (ORCID: https://orcid.org/0000-0003-0671-818X)
- Suzanne Sarah Gisbertz (ORCID: https://orcid.org/0000-0001-9655-7601)
- Rosalia Franco Fernandez (ORCID: https://orcid.org/0000-0002-6409-3918)
- Louis Vermeulen (ORCID: https://orcid.org/0000-0002-6066-789X)
- Jurriaan B. Tuynman (ORCID: https://orcid.org/0000-0001-5952-8000)
- Geert D’Haens (ORCID: https://orcid.org/0000-0003-2784-4046)
- HA Khan
- Adrian Logiantara (ORCID: https://orcid.org/0000-0001-6385-6883)
- Chiara Jongerius (ORCID: https://orcid.org/0000-0001-8814-3679)
- Dennis Poel (ORCID: https://orcid.org/0000-0002-4395-2824)
- Nicole C.T. van Grieken (ORCID: https://orcid.org/0000-0001-9992-0760)
- Andrew Y. F. Li Yim (ORCID: https://orcid.org/0000-0002-0754-0953)
- Marlies P. Schijven (ORCID: https://orcid.org/0000-0001-7013-0116)
- Liming Xiong (ORCID: https://orcid.org/0000-0002-9003-4671)
- N M Mrzlikar
Institutions
- Utrecht University (NL)
- Dutch Cancer Society (NL)
- University Medical Center Utrecht (NL)
- Amsterdam Neuroscience (NL)
- Oncode Institute (NL)
- GGD Amsterdam (NL)
- Amsterdam University Medical Centers (NL)
- Institute of Infection and Immunity (CA)
- Cancer Center Amsterdam (NL)
- Vrije Universiteit Amsterdam (NL)
- University of Amsterdam (NL)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-04-17
- DOI
- https://doi.org/10.1038/s41467-025-58999-6
- Citations
- 8
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 8.36
Funders
- New York Stem Cell Foundation
- ZonMw
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- Oncode Institute