The role of VSIG4-expressing macrophages during peritoneal metastasis formation of colorectal carcinoma

Peritoneal metastasis is a major cause of death for several cancer types, including ovarian, gastric and colorectal carcinoma. In the peritoneal cavity, cancer cells are confronted with locally resident cells, an important part of which are macrophages. This is potentially of relevance, since macrophages have been shown to promote tumor progression at primary and metastatic sites and to mediate resistance to anticancer therapies in a wide range of malignancies. Therefore, therapeutic approaches directed against tumor-associated macrophages are an emerging field of interest. In the current study, we focus on the role of the VSIG4 receptor and VSIG4 macrophages during CRC peritoneal metastasis formation, based on observations that VSIG4 gene expression is
correlated with a worse outcome for CRC and the presence of a subset of VSIG4
macrophages in the peritoneal cavity of mice. Interestingly, these VSIG4-expressing macrophages display a number of activities that are different
from VSIG4-negative peritoneal macrophages. In addition, our data demonstrate that VSIG4 + macrophages are also found in the human peritoneum, as well as in CRC primary tumors and mesenteric metastases, illustrating the potential clinical relevance of this macrophage population.

Based on these intriguing findings, we propose to establish a potential role for either the VSIG4 receptor, or the macrophages expressing this receptor in the establishment and progression of CRC peritoneal metastases.
ence, in the final stage of this PhD, we will (1) assess the role of VSIG4 by analyzing the growth of CRC peritoneal metastases and the peritoneal immune microenvironment in WT versus VSIG4-deficient mice (lack of VSIG4 functionality) or in mice that receive agonistic anti-VSIG4 antibodies (stimulation of VSIG4 functionality), (2) assess the role of VSIG4
peritoneal macrophages by specifically eliminating this population via the use of in-house generated anti-VSIG4-Fc Nanobody (Nb) constructs. If this approach would reduce CRC peritoneal metastasis, we will finally identify a lead anti-humanVSIG4 Nb in our existing anti-VSIG4 Nb library as a basis for future
translational work.

In summary, this study aims to evaluate VSIG4 as a therapeutic target during CRC peritoneal metastasis and will assess anti-VSIG4 Nb constructs as novel therapeutic compounds.