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<p>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 (<i>n</i> = 8). Here we show that the PerIS contains abundant immunosuppressive <i>C1Q</i><sup><i>+</i></sup><i>VSIG4</i><sup><i>+</i></sup> and <i>SPP1</i><sup><i>+</i></sup><i>VSIG4</i><sup><i>+</i></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 <i>IL10</i> and <i>VEGF</i> 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.</p>

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Peritoneal resident macrophages constitute an immunosuppressive environment in peritoneal metastasized colorectal cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月17日

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  • J. Saris,
  • A. Y. F. Li Yim,
  • S. Bootsma,
  • K. J. Lenos,
  • R. Franco Fernandez,
  • H. N. Khan,
  • J. Verhoeff,
  • D. Poel,
  • N. M. Mrzlikar,
  • L. Xiong,
  • M. P. Schijven,
  • N. C. T. van Grieken,
  • O. Kranenburg,
  • M. E. Wildenberg,
  • A. Logiantara,
  • C. Jongerius,
  • J. J. Garcia Vallejo,
  • S. S. Gisbertz,
  • S. Derks,
  • J. B. Tuynman,
  • G. R. A. M. D’Haens,
  • L. Vermeulen,
  • J. Grootjans

摘要

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+VSIG4+ and SPP1+VSIG4+ 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.