Lypd6b promotes colon tumorigenesis by inhibiting CD8+ T cell-mediated anti-tumor immunity through metabolic reprogramming

Lymphocyte antigen-plasminogen activator urokinase receptor domain-containing protein 6B (Lypd6b) is a newly discovered molecule associated with neuromodulation. However, the specific role of Lypd6b in colorectal cancer (CRC) remains unknown. Here, Lypd6b knockout (Lypd6b−/−) mice were generated and an azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colitis-associated colorectal cancer (CAC) model was established. Lypd6b−/− mice are sensitive to DSS-induced colitis but were resistant to AOM/DSS-induced tumorigenesis as evidenced by the decrease in the number and sizes of tumors. Lypd6b deficiency also inhibited MC38 tumor growth. Mechanistically, Lypd6b deficiency promoted activation and function of CD8+ T cells in anti-tumor response with increased glycolysis and reduced oxidative phosphorylation (OXPHOS) in a PI3K/mTOR/LDHA pathway-dependent manner. Furthermore, LYPD6B expression is significantly upregulated in CRC. CRC patients with low Lypd6b expression exhibited increased CD8+ T cell infiltration and altered glycolysis. Thus, Lypd6b as a negative regulator for T cell immunity promotes CRC development, providing a molecular target with therapeutic potential in CRC.