The immune suppressor IGSF1 as a potential target for cancer immunotherapy.

The development of first-generation immune checkpoint inhibitors targeting PD-1/PD-L1 and CTLA-4 ushered in a new era in anticancer therapy. While immune checkpoint blockade therapies have shown clinical success, a significant number of patients yet fail to benefit. According to recent reports, many studies are underway to discover next-generation immunotherapeutic targets. Here, we identified a novel immunotherapeutic target, IGSF1 (immunoglobulin superfamily member 1), by proteome analysis, a membrane glycoprotein proposed to regulate thyroid function. Despite containing 12 immunoglobin domains, a possible role(s) for IGSF1, in immune response, remains unknown. Our studies revealed that IGSF1 is predominantly expressed in tumors but not normal tissues, and increased expression is observed in PD-L1 low NSCLC cells as compared to PD-L1 high cells.Subsequently, we developed and characterized an IGSF1-specific human monoclonal antibody, WM-A1, that effectively promotes anti-tumor immunity and overcomes the limitations of first-generation immune checkpoint inhibitors, likely via a distinct mechanism of action. We further demonstrated high WM-A1 efficacy in humanized peripheral blood mononuclear cells (PBMCs), and syngeneic mouse models, finding synergistic efficacy in combination with an anti-PD-1 antibody (a well-characterized checkpoint inhibitor). These findings support IGSF1 as a novel immune target that might complement existing cancer immunotherapeutics.