IGSF8: A Key Innate Immune Checkpoint and Target for Cancer Immunotherapy

April 30, 2024

Tumor cells often evade the immune system's surveillance, hindering cancer immunotherapy. While adaptive immune evasion mechanisms are well-studied, innate immunity evasion remains less understood. 

Through CRISPR screens, the study by Yulong Li et al. uncovered that IGSF8, typically found in neuronal tissues, suppresses NK cell activity by binding to human KIR3DL2 and mouse Klra9 receptors on NK cells. Despite being non-essential for cell survival, IGSF8 is frequently overexpressed in tumors, correlating with reduced antigen presentation, limited immune cell infiltration, and poorer clinical outcomes. 

Blocking the IGSF8-NK receptor interaction with an antibody boosts NK cell killing of cancer cells in vitro and enhances antigen presentation, NK cell cytotoxicity, and T cell signaling in vivo. In preclinical models, anti-IGSF8 treatment, alone or in combination with anti-PD1, curtails tumor growth. These findings underscore IGSF8 as an innate immune checkpoint and a promising therapeutic target for cancer treatment.

SOURCE: https://www.cell.com/cell/abstract/S0092-8674(24)00355-6#secsectitle0010