Unraveling the complexity of the human peritoneal immune system to find novel targets for peritoneal metastasized cancer

Metastases to the peritoneal cavity are commonly observed in gastrointestinal malignancies, such as in patients with colorectal cancer (CRC) and gastric cancer (GC). This is a devastating condition as peritoneal metastases (PMs) are associated with a dismal prognosis. To better understand current therapy resistance in patients with PM-CRC or PM-GC, we investigated tumor extrinsic factors like the human peritoneal immune system (PerIS) in detail. First, we provide an in depth characterization of the PerIS with the overarching aim to find novel immunomodulatory treatment strategies for patients with peritoneal metastasized disease, a large unmet clinical need. This thesis provides evidence to support that i) the PerIS is a distinct immune system and intrinsically immunosuppressive, ii) peritoneal resident immunosuppressive macrophages actively shape the peritoneal metastatic tumor immune microenvironment in PM-CRC and macrophage depletion in combination with immune checkpoint blockade significantly improves overall survival in preclinical PM models, iii) peritoneal resident memory T cells in PM-GC are dysfunctional and their dysfunctional state is linked to overall survival and iv) humanized immune system mouse models can be used for human subcutaneous, but importantly also peritoneal CRC tumor cell engraftment, and can be used to study tumor cell-T cell interactions in a preclinical setting. Overall, this thesis shows the immunosuppressive nature of the PerIS which appears to facilitate the establishment and progression of peritoneal metastasized disease. Furthermore, these observations suggest that reinvigorating T cells with immune checkpoint blockade is likely more effective when additionally targeting immunosuppressive resident macrophages in the peritoneal cavity.