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

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

51 Scopus citations


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.

Original languageAmerican English
Article numbere000266
JournalJournal for ImmunoTherapy of Cancer
Issue number1
StatePublished - 4 Jun 2020

Bibliographical note

Funding Information:
Funding AR is supported by the Einstein Kaye scholarship. This work was supported by the Israel Innovation Authority (Kamin grant), the Israel Science Foundation (Moked grant), the GIF Foundation, the ICRF professorship grant, the ISF Israel-China grant, and the Ministry of Science and Technology grant (all to O.M.). SJ was supported by the grant 'Strengthening the capacity of CerVirVac for research in virus immunology and vaccinology', KK., awarded to the Scientific Centre of Excellence for Virus Immunology and Vaccines.

Publisher Copyright:
© Author(s) (or their employer(s)) 2020.


  • immunology


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