Abstract 2026: Comprehensive molecular and immunological characterization of CLDN18.2 in pancreatic cancer

Abstract Introduction: Claudin 18 (CLDN18) is an emerging biomarker and transmembrane protein that maintains a tight junction between cells in pancreatic cancer (PC). Due to the high expression of CLDN18.2, an isoform of CLDN18, genomic profiling has demonstrated CLDN18.2 as a potential target with prognostic impact; we aimed to characterize the molecular and immunological features associated with CLDN18.2 expression in PC. Methods: 9, 837 PC samples were tested by NGS (592, NextSeq; WES, NovaSeq) and WTS (NovaSeq; Caris Life Sciences, Phoenix, AZ). PD-L1 expression was assessed using immunohistochemistry (SP142 clone). Immune cell fractions were calculated by deconvolution of WTS: Quantiseq. Tumors with CLDN18.2-high(H) and CLDN18.2-low(L) RNA expression were classified by top and bottom quartile, respectively. Real world overall survival (OS) was obtained from insurance claims and calculated from tissue collection to last contact using Kaplan-Meier estimates. Statistical significance was determined by chi-square and Mann-Whitney U test with p-values adjusted for multiple comparisons (q<0.05). Results: Median CLDN18.2 expression was higher in primary compared to metastatic PC (3-fold, q< 0.05). CLDN18.2-H primary and metastatic PC had higher frequency of KRAS (95.2% vs 83.8%, 91.7% vs. 82.8%) and SMAD4 (28.4% vs 15.3%, 23.1% vs 14.9%), but lower frequency of ARID1A (6.6% vs 11.1%, 8.9% vs 13.2%) mutation (all q<0.05). CLDN18.2-H primary and metastatic PC had lower PD-L1 positivity (4.1% vs 27.9%, 5.3% vs 29.9%, q<0.05). CLDN18.2-H primary and metastatic tumors had higher infiltration of B cells (5.1% vs 3.8%, 4.4% vs 3.3%), M2 Mφ (3.6% vs 3.3%, 3.7% vs 3.1%), and NK cells (2.8% vs 2.5%, 2.5% vs 2.3%), all q<0.05. CLDN18.2-H primary and metastatic PC had differential expression of immune checkpoint genes (upregulation: CTLA4, HAVCR2, FOXP3, CD47, BTLA, TIGIT, CD160; fold change (FC): 1.1 - 1.46; downregulation: CD274, LAG3, IDO1, CD276, FC: 1.1 - 1.3, all q<0.05). CLDN18.2-H primary and metastatic PC had higher T-cell inflamed score (25 vs -28, 21 vs 18.5, q<0.05). CLDN18.2-H was associated with better OS compared to CLDN18.2-L in primary (mOS: 20 vs 13.2 months; HR: 0.73, 95% CI 0.64 - 0.83, p < .00001) and metastatic (mOS: 9.0 vs 5.9 months; HR: 0.76, 95% CI 0.7 - 0.83, p <.00001) PC. A multivariate Cox analysis revealed that above median values of NK cells were strongly associated with better survival in CLDN18.2-H primary (HR: 0.75, 95% CI 0.66 - 0.85, p <.00001) and metastatic (HR: 0.73, 95% CI 0.67 - 0.8, p <.00001) PC. Conclusions: CLDN18.2 expression is associated with distinct genomic alterations, a differentially modulated immune microenvironment and PC patients’ survival. Prospective clinical trials using novel approaches to target CLDN18.2 in PC are underway. Further studies are required to study the impact of CLDN18.2 expression and targeted strategies on survival outcomes of patients with PC. Citation Format: Midhun Malla, Sachin Deshmukh, Timothy Samec, Sharon Wu, Joanne Xiu, Mehmet Akce, Garima Gupta, Qasim Hussaini, Darryl Outlaw, Rebecca Arrend, Aakash Desai, Arnab Basu, Purnachandra N. Ganji, Mark Evans, Heinz-Joseph Lenz, Emil Lou, Dani Castillo, Rachna Schroff, David Spetzler, Bassel El-Rayes. Comprehensive molecular and immunological characterization of CLDN18.2 in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2026.