Implications of secretory leukocyte protease inhibitor expression for patient classification in inflammatory bowel disease and colorectal cancer

SLPI protects against inflammation in the intestine. We found that high colonic epithelial SLPI expression identifies pediatric IBD patients with active clinical disease and strong immune activation characterized by extensive neutrophil infiltration and IL-17A production. Therefore, our data argue that SLPI identifies IBD patients with a strong antimicrobial immune response, which may be related to the underlying pathogenesis. Moreover, high colonic epithelial SLPI expression was associated with previously identified immune profiles related to therapy resistance in IBD, suggesting that SLPI could aid in the identification of IBD patients with therapy nonresponse. Based on the data described in this thesis and the known functions of SLPI, we anticipate that both epithelial and myeloid SLPI production in the intestine during IBD is beneficial to the host. However, experiments using mouse models for intestinal inflammation with conditional knockout for SLPI epithelial or monocytic cells are needed to test these hypotheses.

SLPI can both exert functions promoting and inhibiting cancer. We found that high SLPI expression in CRC liver metastases is associated with poor prognosis after resection of liver metastases, suggesting that detection of SLPI protein expression could aid in predicting prognosis in CRC patients with metastatic disease. In contrast, in patients with stage III MSS CRC, SLPI expression was associated with reduced recurrence of disease. These findings argue that the role of SLPI in CRC may depend on the stage of tumor progression. The association between SLPI expression in CRC liver metastases and poor prognosis and the previously identified role of SLPI in metastasis formation suggest that SLPI expression in CRC may be advantageous for metastatic tumor cells. However, the precise role of SLPI in CRC remains to be established and the results described in this thesis warrant further mechanistic analyses to investigate how SLPI promotes or counteracts human CRC. Therefore, modulation of SLPI expression in human CRC cell lines and orthotopic mouse models for CRC tumor growth and metastasis are needed.