Journal Article

Dipeptidase-1–knockout mice develop invasive tumors with features of microsatellite-unstable colorectal cancer

Zhao, Ping, Xu, Yanwen, Bechard, Matthew E., Aramandla, Radhika, Lau, Ken S., Wang, Yu, Coffey, Robert J., Sievers, Chelsie K., Simmons, Alan J., Fisher, Elizabeth G., Green, Emily H., Irudayam, Maria Johnson, Heiser, Cody N., Revetta, Frank, Liu, Qi, Cao, Zheng, Ellis, Samuel T., Windon, Annika, Washington, M. Kay, Ayers, Gregory D., Shrubsole, Martha J., Glass, Sarah E., Smith, Ryan T., Markham, Nicholas O.

2025

Overview

Dipeptidase-1 (DPEP1) is highly upregulated in colorectal cancer (CRC), with its enzymatic function linked to invasion and metastasis. More recently, DPEP1 was found to serve as a receptor for neutrophils when expressed by activated endothelial cells. It is unknown whether neutrophils bind to DPEP1-expressing CRC cells and whether this impacts features of CRC. Neutrophils have been shown to be tumor promoting in cancers including CRC, where they act to exclude CD8+ T cells. Herein, we show that neutrophils bind DPEP1-expressing CRC cells. In addition, DPEP1 is preferentially expressed in microsatellite-stable (MSS) CRCs, in which there are a paucity of CD8+ T cells, whereas DPEP1 is negatively correlated with microsatellite-unstable (MSI-H) CRCs, which are T cell rich and are more responsive to immunotherapy. Remarkably, carcinogen-treated Dpep1-null mice develop multiple, large, plaque-like, locally invasive adenocarcinomas and squamous cell cancers in the distal colon. These adenocarcinomas exhibit a marked reduction in neutrophils and an influx CD8+ T cells, along with reduced expression of mismatch repair proteins, consistent with features of MSI-H CRC. These results establish DPEP1's importance in maintaining MSS CRC and its ability to shape the tumor microenvironment.

• Publisher: American Society for Clinical Investigation,American Society for Clinical investigation
• Subject: Adenocarcinoma - genetics / Adenocarcinoma - immunology / Adenocarcinoma - pathology / Animals / Biomarkers / Carcinogens / CD8 antigen / CD8-Positive T-Lymphocytes - immunology / Cell biology / Colorectal cancer / Colorectal carcinoma / Colorectal Neoplasms - genetics / Colorectal Neoplasms - immunology / Colorectal Neoplasms - pathology / Dipeptidase / Dipeptidases - genetics / Dipeptidases - metabolism / Endothelial cells / Female / Gene expression / Humans / Immunotherapy / Inflammation / Invasiveness / Leukocytes (neutrophilic) / Lymphocytes / Lymphocytes T / Male / Metastases / Metastasis / Mice / Mice, Knockout / Microsatellite Instability / Mismatch repair / Mutation / Neoplasm Invasiveness / Neutrophils / Neutrophils - immunology / Neutrophils - metabolism / Oncology / Peptides / Proteins / Tumor microenvironment / Tumorigenesis / Tumors / Yeast