RT Journal Article
SR Electronic
T1 Nectin4 is a novel TIGIT ligand which combines checkpoint inhibition and tumor specificity
JF Journal for ImmunoTherapy of Cancer
JO J Immunother Cancer
FD BMJ Publishing Group Ltd
SP e000266
DO 10.1136/jitc-2019-000266
VO 8
IS 1
A1 Adi Reches
A1 Yael Ophir
A1 Natan Stein
A1 Inbal Kol
A1 Batya Isaacson
A1 Yoav Charpak Amikam
A1 Afek Elnekave
A1 Pinchas Tsukerman
A1 Paola Kucan Brlic
A1 Tihana Lenac
A1 Barbara Seliger
A1 Stipan Jonjic
A1 Ofer Mandelboim
YR 2020
UL http://jitc.bmj.com/content/8/1/e000266.abstract
AB Background The use of checkpoint inhibitors has revolutionized cancer therapy. Unfortunately, these therapies often cause immune-related adverse effects, largely due to a lack of tumor specificity.Methods We stained human natural killer cells using fusion proteins composed of the extracellular portion of various tumor markers fused to the Fc portion of human IgG1, and identified Nectin4 as a novel TIGIT ligand. Next, we generated a novel Nectin4 blocking antibody and demonstrated its efficacy as a checkpoint inhibitor in killing assays and in vivo.Results We identify Nectin4 to be a novel ligand of TIGIT. We showed that, as opposed to all other known TIGIT ligands, which bind also additional receptors, Nectin4 interacts only with TIGIT. We show that the TIGIT-Nectin4 interaction inhibits natural killer cell activity, a critical part of the innate immune response. Finally, we developed blocking Nectin4 antibodies and demonstrated that they enhance tumor killing in vitro and in vivo.Conclusion We discovered that Nectin4 is a novel ligand for TIGIT and demonstrated that specific antibodies against it enhance tumor cell killing in vitro and in vivo. Since Nectin4 is expressed almost exclusively on tumor cells, our Nectin4-blocking antibodies represent a combination of cancer specificity and immune checkpoint activity, which may prove more effective and safe for cancer immunotherapy.