Glass, Sarah E.; Bechard, Matthew E.; Cao, Zheng; Aramandla, Radhika; Zhao, Ping; Ellis, Samuel T.; Green, Emily H.; Fisher, Elizabeth G.; Smith, Ryan T.; Sievers, Chelsie K.; Irudayam, Maria Johnson; Revetta, Frank; Washington, M. Kay; Ayers, Gregory D.; Heiser, Cody N.; Simmons, Alan J.; Xu, Yanwen; Wang, Yu; Windon, Annika; Shrubsole, Martha J.; Markham, Nicholas O.; Liu, Qi; Lau, Ken S.; Coffey, Robert J. “Dipeptidase-1–knockout mice develop invasive tumors with features of microsatellite-unstable colorectal cancer.” JCI Insight 10, no. 9 (2025): e186938. https://doi.org/10.1172/jci.insight.186938.
Dipeptidase-1 (DPEP1) is a protein found at high levels in colorectal cancer (CRC), and it’s known to help cancer cells spread and invade other tissues. Recently, scientists discovered that DPEP1 can also act as a receptor that allows neutrophils—a type of immune cell—to attach when DPEP1 is present on blood vessel cells. However, it wasn’t clear whether neutrophils can also stick to cancer cells that produce DPEP1, or how that might affect the cancer.
In this study, researchers show that neutrophils do bind to CRC cells that express DPEP1. DPEP1 is found more often in a type of CRC called microsatellite-stable (MSS), which tends to have fewer cancer-fighting CD8+ T cells and usually responds poorly to immunotherapy. In contrast, DPEP1 is less common in microsatellite instability-high (MSI-H) CRCs, which have more T cells and are more likely to respond to immune-based treatments.
Interestingly, when mice that lack the Dpep1 gene were exposed to a cancer-causing chemical, they developed large, aggressive tumors in the lower colon. These tumors had fewer neutrophils, more CD8+ T cells, and lower levels of DNA repair proteins—features typical of MSI-H CRC.
These findings show that DPEP1 not only helps define the MSS form of CRC but also plays a key role in shaping the immune environment around the tumor.
Figure 1
DPEP1 is linked to neutrophil presence and binding in CRC.
(A) Hematoxylin and eosin (H&E) staining and DPEP1 and neutrophil elastase immunohistochemistry (IHC) for 2 selected cores from a human adenoma tissue microarray (TMA) (n = 336 cores assessed). (B) DPEP1 and neutrophil elastase IHC and H&E for a selected core from a human CRC TMA (n = 249 cores assessed). (C) Quantification of neutrophil binding assay for comparison of SW480 and SW620 cells, where each field of view (FOV) is an individual data point (n = 12 FOVs per cell type). (D) Quantification of neutrophil binding assay for SW620 cells treated with scrambled or LSALT peptide at the designated concentrations (μM) as indicated on the graph, where each FOV is an individual data point (n = 12 FOVs per condition). Data are representative images. Arrows mark individual cells positive for neutrophil elastase. Scale bars: 200 μm and 100 μm (insets). Binding assays were conducted in triplicate. Error bars represent SEM. NS, no significance. ***P < 0.001; ****P < 0.0001 by Wilcoxon-Mann-Whitney (C) andor Kruskal-Wallis test (D).
