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. 2025 Dec 9;11(2):e194290.
doi: 10.1172/jci.insight.194290. eCollection 2026 Jan 23.

Nectin-4 reduces T cell effector function and is a therapeutic target in pancreatic cancer

Max Heiduk  1   2   3   4   5 , Carolin Beer  1 , Sarah Cronjaeger  1   2   3   4   5 , Emily A Kawaler  6 , Ulrich Sommer  7   8 , Franziska Baenke  1   2   3   4   5   9 , David Digomann  1   2   3   4   5   9 , Loreen Natusch Bufe  1   2   3   4   5   9 , Charlotte Reiche  1   2   3   4   5 , Jessica Glück  1 , Franziska Hoffmann  1 , Sungsik Kim  10 , Daniel E Stange  1   2   3   4   5   9 , Diane M Simeone  10 , Jürgen Weitz  1   2   3   4   5   9 , Lena Seifert  1   2   3   4   5   9   11 , Adrian M Seifert  1   2   3   4   5   9
Affiliations

Nectin-4 reduces T cell effector function and is a therapeutic target in pancreatic cancer

Max Heiduk et al. JCI Insight. .

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.

Keywords: Cancer; Gastroenterology; Oncology; T cells.

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Figures

Figure 1
Figure 1. TIGIT, CD226, and CD96 are expressed by tumor-infiltrating T cells.
(A) Representative contour flow plots for expression of TIGIT and percentage of TIGIT by CD8+ T cells, Tconv, and Treg in matched blood and PDAC (n = 84). (B) Representative contour flow plots for expression of CD226 and percentage of CD226 by CD8+ T cells, Tconv and Treg in matched blood and PDAC (n = 19). (C) Representative contour flow plots for expression of CD96 and percentage of CD96 by CD8+ T cells, Tconv, and Treg in matched blood and PDAC (n = 19). Each point represents data from 1 patient. Medians are shown as horizontal red lines. Paired 2-tailed t tests with Holm-Šídák correction were used. (D) Stacked columns showing the mean coexpression of TIGIT, CD226, and CD96 among CD8+ T cells, Tconv, and Treg (from left to right) in blood versus PDAC. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. (E) Heatmap showing Pearson correlation coefficient (rPearson) for correlation between ICR expressions by indicated T cell subsets in blood (left) and PDAC (right). To correct for multiple comparisons in correlation analysis, significance levels were set at *P < 0.01; **P < 0.001.
Figure 2
Figure 2. Nectin-4 expression is associated with poor outcome in PDAC.
(A) Representative images of CD155 (top) and Nectin-4 (bottom) IHC staining with low and high intensity. Scale bar: 100 μm. (B) Dot plot showing the distribution of immune reactive scores (IRS; CD155, n = 69; Nectin-4, n = 68). (C) Stacked columns depicting the proportion of patients with CD155 and Nectin-4 expression according to intensity. (D) Kaplan-Meier analysis of overall survival of R0-resected patients with PDAC according to low or high CD155 (left) or Nectin-4 (right) expression. P values of log rank test are indicated. (E) Table and forest plot depicting survival hazard ratios (HR) with 95% CI of CD155 and Nectin-4 IRS in multivariate Cox proportional hazards regression analysis including both R0- and R1-resected patients, shown as a function of clinicopathological parameters. *P < 0.05; **P < 0.01.
Figure 3
Figure 3. CD155 expression is associated with reduced TIGIT expression by PDAC-infiltrating Tconv and Tregs.
(A and B) Percentage of T cells among all immune cells (left) and percentage of indicated T cell subsets among all T cells (right) in blood (A) and PDAC (B) for low and high CD155 expression (n = 69). (C and D) Percentage of TIGIT, CD226 and CD96 expression (from left to right) for indicated T cell subsets in blood (C) and PDAC (D) for low and high CD155 expression. Each point represents data from 1 patient. Medians are shown as horizontal lines. Unpaired 2-tailed t tests with Holm-Šídák correction. **P < 0.01; ***P < 0.001.
Figure 4
Figure 4. Nectin-4 expression is associated with reduced immune cell infiltration in PDAC.
(A and B) Percentage of T cells among all immune cells (left) and percentage of indicated T cell subsets among all T cells (right) in blood (A) and PDAC (B) for low and high Nectin-4 expression (n = 68). (C and D) Percentage of TIGIT, CD226 and CD96 expression (from left to right) for indicated T cell subsets in blood (C) and PDAC (D) for low and high Nectin-4 expression. Each point represents data from 1 patient. Medians are shown as horizontal lines. Unpaired 2-tailed t tests with Holm-Šídák correction. *P < 0.05.
Figure 5
Figure 5. Nectin-4 is exclusively expressed by tumor cells in PDAC.
(A) Dot plot depicting gene expression of TIGIT family receptors and ligands in several compartments within human primary PDAC (n = 17). The dot size represents the percentage of cells expressing the gene, and the color represents the average expression within those cells. (B) Violin plot of PVRL4 expression in all malignant epithelial cells in primary PDAC (n = 11) compared with PDAC liver metastases (n = 9) from treatment-naive patients. (C) Scatter plot showing the correlation between PVRL4 expression in malignant epithelial cells and percentage of T cells among all analyzed cells per sample in treatment-naive (n = 11) and chemotherapeutically-treated (n = 6) primary PDAC. Pearson correlation coefficients and P values are depicted. Each dot represents 1 sample. Wilcoxon signed-rank test for comparison of expression levels. ****P < 0.0001.
Figure 6
Figure 6. Enfortumab vedotin has antitumor efficacy in PDAC PDOs.
(A) IFN-γ and TNF-α production by peripheral T cells from patients with PDAC after in vitro stimulation with anti-CD3 and anti-CD28 in the presence of plate-bound (pb, n = 8) or soluble (s, n = 4) Nectin-4. Each point represents data from 1 patient. Data are shown as mean ± SD. Unpaired 2-tailed t tests with Welch’s correction. *P < 0.05; **P < 0.001; ***P < 0.001; ****P < 0.0001. (B) Representative expression level of PVRL4 by qPCR (bars indicate mean of technical duplicates). (C) Nectin-4 expression in PDAC PDOs by Western blot. (D) Dose response curves from PDAC PDOs treated with FOLFIRINOX, gemcitabine plus paclitaxel (Gem/Pac), or enfortumab vedotin. The relative viability in percentage at a given drug concentration of 2 independent biological replicates is shown. (E) Z scores generated from relative AUC from dose response curves from PDAC PDOs either treated with FOLFIRINOX, Gem/Pac, or enfortumab vedotin. (F) Representative images of 2 PDAC PDOs either treated with the standard regimen FOLFIRINOX, Gem/Pac, or enfortumab vedotin. PDOs were stained with caspase-3 dye profiling apoptosis (green) and imaged after 3 days. Scale bar: 50 μm.
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References

    1. Siegel RL, et al. Cancer statistics, 2023. CA Cancer J Clin. 2023;73(1):17–48. doi: 10.3322/caac.21763. - DOI - PubMed
    1. Ho WJ, et al. The tumour microenvironment in pancreatic cancer - clinical challenges and opportunities. Nat Rev Clin Oncol. 2020;17(9):527–540. doi: 10.1038/s41571-020-0363-5. - DOI - PMC - PubMed
    1. Yousuf S, et al. Spatially resolved multi-omics single-cell analyses inform mechanisms of immune dysfunction in pancreatic cancer. Gastroenterology. 2023;165(4):891–908. doi: 10.1053/j.gastro.2023.05.036. - DOI - PubMed
    1. Muller M, et al. The immune landscape of human pancreatic ductal carcinoma: key players, clinical implications, and challenges. Cancers (Basel) 2022;14(4):995. doi: 10.3390/cancers14040995. - DOI - PMC - PubMed
    1. Chiang EY, Mellman I. TIGIT-CD226-PVR axis: advancing immune checkpoint blockade for cancer immunotherapy. J Immunother Cancer. 2022;10(4):e004711. doi: 10.1136/jitc-2022-004711. - DOI - PMC - PubMed

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