The Immune Suppressor IGSF1 as a Potential Target for Cancer Immunotherapy.
Dong-In KohMinki LeeYoon Sun ParkJae-Sik ShinJoseph KimYea Seong RyuJun Hyung LeeSeunggeon BaeMi So LeeJun Ki HongHong Rae JeongMingee ChoiSeung-Woo HongDong Kwan KimHyun-Kyung LeeBomi KimYoo Sang YoonDong-Hoon JinPublished in: Cancer immunology research (2024)
The development of first-generation immune-checkpoint inhibitors targeting PD-1/PD-L1 and CTLA-4 ushered in a new era in anticancer therapy. Although immune-checkpoint blockade therapies have shown clinical success, a substantial number of patients yet fail to benefit. Many studies are under way to discover next-generation immunotherapeutic targets. Immunoglobulin superfamily member 1 (IGSF1) is a membrane glycoprotein proposed to regulate thyroid function. Despite containing 12 immunoglobin domains, a possible role for IGSF1, in immune response, remains unknown. Here, our studies revealed that IGSF1 is predominantly expressed in tumors but not normal tissues, and increased expression is observed in PD-L1low non-small cell lung cancer (NSCLC) cells as compared with PD-L1high cells. Subsequently, we developed and characterized an IGSF1-specific human monoclonal antibody, WM-A1, that effectively promoted antitumor immunity and overcame 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 (PBMC), and syngeneic mouse models, finding additive efficacy in combination with an anti-PD-1 (a well-characterized checkpoint inhibitor). These findings support IGSF1 as an immune target that might complement existing cancer immunotherapeutics.
Keyphrases
- monoclonal antibody
- induced apoptosis
- immune response
- cell cycle arrest
- small cell lung cancer
- endothelial cells
- end stage renal disease
- mouse model
- ejection fraction
- dna damage
- poor prognosis
- newly diagnosed
- gene expression
- papillary thyroid
- case control
- dendritic cells
- signaling pathway
- endoplasmic reticulum stress
- risk assessment
- toll like receptor
- single cell
- cancer therapy
- epidermal growth factor receptor
- advanced non small cell lung cancer
- young adults
- cell therapy
- lymph node metastasis
- genome wide identification
- human health
- bone marrow
- binding protein
- smoking cessation
- replacement therapy