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ORIGINAL RESEARCH article

Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1415457

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

Provisionally accepted
Job Saris Job Saris 1Sanne Bootsma Sanne Bootsma 1Jan Verhoeff Jan Verhoeff 2Jurriaan B. Tuynman Jurriaan B. Tuynman 1,3Manon Wildenberg Manon Wildenberg 2Esther Siteur-Van Rijnstra Esther Siteur-Van Rijnstra 4Kristiaan J. Lenos Kristiaan J. Lenos 1Juan J. Garcia-Vallejo Juan J. Garcia-Vallejo 1Louis Vermeulen Louis Vermeulen 5Joep Grootjans Joep Grootjans 1*
  • 1 Other, Amsterdam, Netherlands
  • 2 Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Center (UMC), Amsterdam, Netherlands
  • 3 Amsterdam University Medical Center, Amsterdam, Netherlands
  • 4 University of Amsterdam, Amsterdam, Netherlands
  • 5 Oncode Institute, Amsterdam, Netherlands

The final, formatted version of the article will be published soon.

    The 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 preclinical potential of a humanized immune system (HIS) mouse model for PM-CRC.We studied the human PerIS in PM-CRC patients (n=20; MSS 19/20; 95%) and in healthy controls (n=3). HIS mice (NOD-scid 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).The 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. In conclusion, T cell responses in PM-CRC in HIS mice mirror those in human PM-CRC, making this model suitable to study anti-tumor T cell responses in PM-CRC.

    Keywords: colorectal cancer, Peritoneal metastasis, peritoneal immune system, humanized immune system, his, T-cell biology, cyTOF

    Received: 10 Apr 2024; Accepted: 21 Jun 2024.

    Copyright: © 2024 Saris, Bootsma, Verhoeff, Tuynman, Wildenberg, Siteur-Van Rijnstra, Lenos, Garcia-Vallejo, Vermeulen and Grootjans. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Joep Grootjans, Other, Amsterdam, Netherlands

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.