Nectin4 is a novel TIGIT ligand which combine checkpoint inhibition and tumor specificity

Adi Reches ¹ Yael Ophir ¹ Natan Stein ¹ Inbal Kol ¹ Batya Isaacson ¹ Yoav Charpak Amikam ¹ Afek Elnekave ¹ Pinchas Tsukerman ¹ Paola Kucan Brlic ² Tihana Lenac ² Barbara Seliger ³ Stipan Jonjic ² Ofer Mandelboim ¹

¹Immunology, The Hebrew University Medical School, Israel
²Department of Histology and Embryology, University of Rijeka, Croatia
³Institute of Medical Immunology, Martin-Luther-University Halle-Wittenberg, Germany

The use of checkpoint inhibitors antibodies has revolutionized cancer therapy. Unfortunately, these therapies often cause immune-related adverse effects, largely due to a lack of tumor specificity. We examined tumor-markers for checkpoint activity and found that Nectin4 is a novel ligand of TIGIT, a powerful inhibitory receptor, and is the only Nectin family member that interacts with TIGIT alone. We show that the TIGIT-Nectin4 interaction inhibits natural killer cell activity, a critical part of the tumor immune response. We developed blocking Nectin4 antibodies and demonstrate that they enhance tumor killing. Thus, our Nectin4-blocking antibodies represent a unique synergy between pure inhibitory effect, cancer specificity, and immune checkpoint activity, which may prove effective and safe as cancer immunotherapy.