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

Abstract

BackgroundThe 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.MethodsWe 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.ResultsWe 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.ConclusionWe 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.

Spatial drivers and pre-cancer populations collaborate with the microenvironment in untreated and chemo-resistant pancreatic cancer

“…Receptor-ligand analyses furthermore reveal an interaction between the TIGIT receptor in lymphocytes and its NECTIN2 receptor across all samples, which we found is highly expressed in tumor cells ( STAR Methods ). This is consistent with a previous report that NECTIN4 has high tumor specificity and is a potential target for immune checkpoint blockade (Reches et al, 2020; Gorvel and Olive, 2020). TIGIT interaction with NECTIN receptors inactivates T cell and NK function, which could be used by the tumor for immune evasion.…”

“…Furthermore, we observe that PD-L1 and PD-L2 are not expressed in tumor cells at all, consistent with the poor response of PDAC to anti-PD-1/PD-L1 immunotherapy (Feng et al, 2017;Birnbaum et al, 2016;Pu et al, 2019). We extend our analysis of nectin receptors to all cell types to assess tumor-specific expression beyond lymphocytes and note that while nectins are overall quite tumor-specific, NECTIN1 is highly expressed in myCAFs, NECTIN2 in endothelial cells, and NECTIN3 in islet cells; NECTIN4 is the most tumor cell-specific NECTIN receptor ( Figure 6F), consistent with previous reports (Reches et al, 2020). We analyzed TIGIT and Nectin receptors expression at individual sample levels in Tregs, NK cells, exhausted T cells, and tumor cells ( Figure 6G).…”

Hitting the complexity of the TIGIT-CD96-CD112R-CD226 axis for next-generation cancer immunotherapy

“…Nectin-4 has recently been reported as a ligand that interacts with TIGIT alone. Nectin-4 expression is restricted to cancer cells, and Nectin-4 blockade improves the NK cell-mediated antitumor response in mice ( 31 ).…”

High-Grade Serous Ovarian Tumor Cells Modulate NK Cell Function to Create an Immune-Tolerant Microenvironment

“…The copyright holder for this preprint this version posted November 21, 2020. ; https://doi.org/10.1101/2020.11.20.391706 doi: bioRxiv preprint receptor TIGIT and, in a separate study nectin 4 expression was proposed to have a role in HGSC metastasis and chemotherapeutic resistance (Derycke et al, 2010;Reches et al, 2020). Furthermore, both nectin 4 and CD111 have additional roles in adhesion, cell movement and stem cell biology (Belaaloui et al, 2003;Martinet and Smyth, 2015;Yurtsever et al, 2013).…”