Research on the Mechanism of Lphn1 Knockout in Inhibiting Colorectal Cancer

Abstract

AbstractDecades ago, colorectal cancer was rarely diagnosed. Today, it is the fourth leading cause of cancer-related deaths worldwide, with nearly 90,000 fatalities each year.By analyzing single-cell data from tumor-bearing colorectal cancer model mice with Lphn1 knockout and wild-type Lphn1, we identified five key target genes for anticancer therapy: Ulbp1, Klrk1, Ccl6, Tlr4, Cd48, Prdm5, VSTM2A, RET, OAS2, Hdac11 and Ptchd4, along with their corresponding cell types. Additionally, we discovered tumor-inhibiting cell subpopulations, including Cd244a_T_cells_subcluster_1, Cd48_Cd244a_NK_cells_subcluster_2, and C3_Macrophages_subcluster_1, which are potential candidates for therapeutic intervention. We propose that cancer-associated fibroblasts (CAFs) serve as the primary antigen presenters for MHC class I, providing antigens to macrophages, NK cells, and T cells to combat colorectal cancer. From a cellular perspective, the knockout of Lphn1 activates the anti-colorectal cancer functions of subpopulations of macrophages, NK cells, and T cells. Macrophages enhance antitumor immune activity by engaging the Ulbp1-Klrk1 receptor pair to activate NK cells. Additionally, macrophages activate downstream functions of T cells against colorectal cancer through CD48 signaling. After the knockout of Lphn1, macrophages are recruited by autocrine Ccl6 and Ccl6 secreted by CAFs. They exhibit high expression of Tlr4 and have the potential to transition into M1-type macrophages due to changes in their cellular state. After the knockout of Lphn1, the CAFs were reduced by half. CAFs, which are part of the cell network communication associated with tumor cells, typically play an immunosuppressive role. A reduction by half indicates that the immunosuppression in the Lphn1 knockout group has significantly decreased. This suggests that the efficacy of various cancer immunotherapy drugs can be significantly enhanced. These findings could open new avenues for the treatment of colorectal cancer and contribute to the development of personalized medicine.