Submit a comment
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis, and current therapies show limited efficacy. Ligands and receptors of the TIGIT axis were analyzed using multicolor flow cytometry of tumor and blood samples, IHC from primary tumors, and single-cell RNA-Seq from primary tumors and liver metastasis from patients with various stages of PDAC. The effect of soluble and plate-bound Nectin-4 on T cell function was tested in vitro. Furthermore, patient-derived PDAC organoids were treated with the standard-of-care therapies FOLFIRINOX, gemcitabine plus paclitaxel, or the antibody-drug conjugate enfortumab vedotin. TIGIT expression was increased on tumor-infiltrating conventional T cells and Tregs compared with T cells from matched blood. Nectin-4 but not CD155 expression was associated with poor outcome. Nectin-4 was exclusively expressed by tumor cells and correlated with low immune infiltration. Notably, Nectin-4 inhibited T cell effector cytokine production in vitro. Targeting Nectin-4 with the antibody-drug conjugate enfortumab vedotin inhibited tumor growth in multiple patient-derived PDAC organoids. Collectively, our data underscore Nectin-4 as a potential novel therapeutic target and provide the rationale to test this agent in patients with PDAC.
Authors
Max Heiduk, Carolin Beer, Sarah Cronjaeger, Emily A. Kawaler, Ulrich Sommer, Franziska Baenke, David Digomann, Loreen Natusch Bufe, Charlotte Reiche, Jessica Glück, Franziska Hoffmann, Sungsik Kim, Daniel E. Stange, Diane M. Simeone, Jürgen Weitz, Lena Seifert, Adrian M. Seifert
Guidelines
The Editorial Board will only consider comments that are deemed relevant and of interest to readers. The Journal will not post data that have not been subjected to peer review; or a comment that is essentially a reiteration of another comment.
- Comments appear on the Journal’s website and are linked from the original article’s web page.
- Authors are notified by email if their comments are posted.
- The Journal reserves the right to edit comments for length and clarity.
- No appeals will be considered.
- Comments are not indexed in PubMed.
Specific requirements
- Maximum length, 400 words
- Entered as plain text or HTML
- Author’s name and email address, to be posted with the comment
- Declaration of all potential conflicts of interest (even if these are not ultimately posted); see the Journal’s conflict-of-interest policy
- Comments may not include figures
