Abstract 7295: Reversing resistance to checkpoint inhibitors by treatment with claudin-1 specific antibodies in an orthotopic in vivo model for cholangiocarcinoma

Abstract Background: Resistance to immunotherapy is a major challenge in the treatment of solid tumors. Cholangiocarcinoma (CCA) exemplifies this challenge by poor outcome and very limited response to approved checkpoint inhibitors (CPI). Claudin-1 (CLDN1) is a transmembrane protein overexpressed in epithelial cancer cells and shown to be a mediator of carcinogenesis, invasion and metastasis. However, the functional role of CLDN1 for the tumor microenvironment (TME) is largely unknown. Using CCA as a model disease, we aimed to study the impact of CLDN1 for the TME and its potential role as a therapeutic target to address CPI resistance. Methods: CLDN1 expression and its association with TME was analyzed by spatial transcriptomics in CCA patient tissues. Immunocompetent orthotopic animal models of intrahepatic CCA were generated by hydrodynamic tail vein injection (HDTV) of proto-YAP/AKT or the KRAS/p19 oncogenes together with a CLDN1 expressing plasmid. Following tumor development within the liver, mice were treated with monoclonal antibodies (mAbs) targeting CLDN1 and/or PD-1. Results: Spatial analyses of patient tissues revealed that CLDN1 was overexpressed in cancer cells and CLDN1 expression was associated with oncogenic signaling and reduced T cell infiltration. In orthotopic mouse models for CCA, CLDN1 gain-of-function studies showed enhanced tumor growth and decreased survival. Treatment with CLDN1 mAbs markedly and significantly reduced tumor burden and intratumoral fibrosis and resulted in increased intratumoral CD3+ and CD8+ T cell infiltration as well as modulation of peritumoral macrophage distribution. Gene expression analyses revealed down-regulation of pathways for fibrogenesis, carcinogenesis and up-regulation of pathways for T cell activation and proliferation. Whereas PD1 mAb single agent therapy did not show significant efficacy, the combination of PD-1 with CLDN1 mAbs markedly and significantly improved overall survival. Conclusions: CLDN1 plays a functional role in the TME by modulating tumor fibrosis and immune cell infiltration. Treatment with CLDN1 mAbs provides an opportunity to overcome resistance and improve the efficacy of CPIs by enhancing tumoral immune responses. Citation Format: Romain Desert, Zeina Nehme, Bocar Kane, Emilie Crouchet, Frank Jühling, Vikas Ranvir, Alberto Toso, Mathias Heikenwälder, Catherine Schuster, Thomas Baumert. Reversing resistance to checkpoint inhibitors by treatment with claudin-1 specific antibodies in an orthotopic in vivo model for cholangiocarcinoma [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 7295.