Frontiers in Immunology (Jul 2024)

T-cell responses in colorectal peritoneal metastases are recapitulated in a humanized immune system mouse model

  • Job Saris,
  • Job Saris,
  • Job Saris,
  • Job Saris,
  • Job Saris,
  • Sanne Bootsma,
  • Sanne Bootsma,
  • Sanne Bootsma,
  • Sanne Bootsma,
  • Jan Verhoeff,
  • Jan Verhoeff,
  • Jan Verhoeff,
  • Jan Verhoeff,
  • Jan Verhoeff,
  • Jan Verhoeff,
  • Jurriaan B. Tuynman,
  • Jurriaan B. Tuynman,
  • Manon E. Wildenberg,
  • Manon E. Wildenberg,
  • Manon E. Wildenberg,
  • Esther Siteur-van Rijnstra,
  • Kristiaan J. Lenos,
  • Kristiaan J. Lenos,
  • Kristiaan J. Lenos,
  • Kristiaan J. Lenos,
  • Juan J. Garcia Vallejo,
  • Juan J. Garcia Vallejo,
  • Juan J. Garcia Vallejo,
  • Louis Vermeulen,
  • Louis Vermeulen,
  • Louis Vermeulen,
  • Louis Vermeulen,
  • Joep Grootjans,
  • Joep Grootjans,
  • Joep Grootjans,
  • Joep Grootjans,
  • Joep Grootjans

DOI
https://doi.org/10.3389/fimmu.2024.1415457
Journal volume & issue
Vol. 15

Abstract

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BackgroundThe occurrence of peritoneal metastasis (PM) in patients with colorectal cancer (CRC) has a dismal prognosis. There is often limited response to systemic- and immunotherapy, even in microsatellite unstable (MSI) CRC. To overcome therapy resistance, it is critical to understand local immune environment in the peritoneal cavity, and to develop models to study anti-tumor immune responses. Here, we defined the peritoneal immune system (PerIS) in PM-CRC patients and evaluate the pre-clinical potential of a humanized immune system (HIS) mouse model for PM-CRC.MethodsWe studied the human PerIS in PM-CRC patients (n=20; MSS 19/20; 95%) and in healthy controls (n=3). HIS mice (NODscid gamma background; n=18) were generated, followed by intraperitoneal injection of either saline (HIS control; n=3) or human MSS/MSI CRC cell lines HUTU80, MDST8 and HCT116 (HIS-PM, n=15). Immune cells in peritoneal fluid and peritoneal tumors were analyzed using cytometry by time of flight (CyTOF).ResultsThe human and HIS mouse homeostatic PerIS was equally populated by NK cells and CD4+- and CD8+ T cells, however differences were observed in macrophage and B cell abundance. In HIS mice, successful peritoneal engraftment of both MSI and MSS tumors was observed (15/15; 100%). Both in human PM-CRC and in the HIS mouse PM-CRC model, we observed that MSS PM-CRC triggered a CD4+ Treg response in the PerIS, while MSI PM-CRC drives CD8+ TEMs responses.ConclusionIn conclusion, T cell responses in PM-CRC in HIS mice mirror those in human PM-CRC, making this model suitable to study antitumor T cell responses in PM-CRC.

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