RNA-seg of CD8+ T cells from colorectal cancer tumor tissues in wildtype and  Lypd6-/- mice
RNA-sequencing analyses were performed in CD8+ T cells sorted from MC38 tumors of WT and Lypd6b-/- mice, To investigate the effects of Lypd6b gene knockout on CD8+ T cells in the colon cancer tumor microenvironment. Abstract Lypd6b is a newly discovered molecule associated with neuromodulation. However, the effects of Lypd6b on the tumor microenvironment and its impact on CD8+ T cell-mediated antitumor immunity remain unknown. Here, we observe that Lypd6b expression is increased significantly in colorectal cancer (CRC) tumor tissues compared to normal tissues. Lypd6b is mainly expressed in CD8+ T cells in tumor tissues. Lypd6b knockout (Lypd6b-/-) mice are resistant to AOM/DSS-induced tumorigenesis. Furthermore, global deficiency or CD8+ cell deficiency of Lypd6b (CD8Lypd6b-/-) inhibits MC38 or CMT-93 tumor growth and promotes the infiltration of CD8+ T cells. Mechanistically, Lypd6b deficiency promotes 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. Notably, Lypd6b deficient CD8+ T cells have a more potent antitumor effect when combined with anti-PD1 antibody. Thus, Lypd6b as a negative regulator for T cell immunity promotes CRC development, providing a molecular target with therapeutic potential in CRC.