Abstract A003: DPEP1 maintains microsatellite stability in colorectal cancer at the tumor microenvironment interface

Abstract DPEP1 is a well-established GPI-linked dipeptidase whose expression is highly upregulated in colorectal cancer (CRC). Its enzymatic function includes extracellular processing of glutathione and leukotrienes, which has been linked to invasion and metastasis in CRC. More recently, it 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 accumulate and exclude cytotoxic CD8+ T cells in CRC with DPEP1 being identified as a key gene in immune exclusion that has not been functionally evaluated. Herein, we show that neutrophils bind CRC cells that express DPEP1 and that DPEP1 is preferentially expressed in microsatellite stable CRCs, in which there are a paucity of CD8+ T cells. In contrast, DPEP1 is negatively correlated with microsatellite unstable CRCs, which are T cell-rich and have a much higher propensity to respond to immunotherapy. Notably, carcinogen-treated DPEP1 null mice develop multiple, large, plaque-like, locally invasive adeno-squamous carcinomas with markedly reduced DNA repair protein expression and neutrophil presence but exhibited an influx of CD8+ T cell within the tumor. These results establish DPEP1’s importance in maintaining MSS CRC and its ability to shape the tumor microenvironment. Citation Format: Sarah Glass, Matthew Bechard, Zheng Cao, Radhika Aramnadla, Ping Zhao, Samuel Ellis, Elizabeth Fisher, Frank Revetta, M. Kay Washington, Gregory Ayers, Cody Heiser, Annika Windon, Nicholas Markham, Martha Shrubsole, Ken Lau, Robert J Coffey. DPEP1 maintains microsatellite stability in colorectal cancer at the tumor microenvironment interface [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr A003.