Abstract 1585: Tenascin C in pancreatic cancer-associated fibroblasts enhances epithelial mesenchymal transition and is associated with resistance to immune checkpoint inhibitor

Abstract

Abstract Backgrounds: Tenascin C (TNC) is an extracellular matrix glycoprotein that is abundantly expressed in cancer stroma and its overexpression correlates with tumor progression in various types of cancer including pancreatic adenocarcinoma (PAAD). However, the role of TNC in regards to response to immune checkpoint inhibitor (ICI) still remains to be identified. In this study, we aimed to investigate the potential involvement of TNC in the response to ICI among PAAD patients. Materials and Methods: Transcriptomic profiles were downloaded by TCGA and GTEx database and TNC mRNA levels were compared between tumors and normal tissues. These transcriptomic data were deconvoluted using CIBERSORTx to identify specific enriched pathways in cancer cells and cancer-associated fibroblasts (CAFs) in PAAD patients. Bioinformatic programs were used to predict paracrine communications between cancer cells and cancer-associated fibroblasts (CAFs), and the Tumor Immune Dysfunction and Exclusion (TIDE) score was calculated to predict response to ICI treatment in PAAD patients. An independent immunotherapeutic cohort was applied to validate prediction values for immunotherapy. Results: TNC mRNA levels were significantly upregulated in tumors compared to normal tissues in eight cancer types including PAAD. TNC-high (TNC-H) PAAD patients (n = 138) had significant shorter overall survival than TNC-low (TNC-L) patients (n = 40) (p = 0.0125, Log-rank test). Using CIBERSORTx, TNC was estimated to be predominantly expressed in CAFs in PAAD. In pathway analysis, both cancer cells and CAFs had significant enrichments of the epithelial mesenchymal transition pathway in TNC-H patients. Ligand-receptor interaction analysis showed that TNC produced in CAFs had the highest interaction potentials to bind to integrin families such as ITGαV and ITGβ3 in cancer cells. In an independent immunotherapy data cohort, patients with TNC-H and ITGαV-high or ITGβ3-high expression were associated with poor response to ICI treatment and had shorter overall survival than those with both low expressions. Conclusions: In conclusion, these findings suggest that TNC-high CAFs can play a crucial role in tumor progression and resistance to ICI therapy in PAAD patients, and targeting TNC and its interactions with cancer cells may provide a potential strategy for improving the efficacy of ICI therapy in PAAD. Citation Format: Satoru Furuhashi, Yoshifumi Morita, Akio Matsumoto, Shinya Ida, Ryuta Muraki, Ryo Kitajima, Makoto Takeda, Hirotoshi Kikuchi, Yoshihiro Hiramatsu, Hiroya Takeuchi. Tenascin C in pancreatic cancer-associated fibroblasts enhances epithelial mesenchymal transition and is associated with resistance to immune checkpoint inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1585.