IDDF2024-ABS-0407 Tight junction protein CLDN9 promotes colorectal cancer liver metastasis via loss of MHC class I antigen presentation

Background Most patients with colorectal cancer (CRC) develop liver metastases during disease progression, but the key molecular mechanisms leading to CRC metastasis remain unclear. Claudins are frequently associated with various cancers. Here, we investigated the transmembrane tight junction protein Claudin9 (CLDN9) as a therapeutic target associated with colorectal cancer liver metastases. Methods We constructed a mouse model of hepatic metastasis of CRC by cecal implantation of a mouse adenocarcinoma cell line in an immune-competent host. Then, by in vivo selection, we isolated cells of varying metastatic potential. A tissue microarray (TMA) comprising 221 pairs of CRC tissues and adjacent normal tissues was used to study the correlation between CLDN9 expression and CRC metastasis. The role of CLDN9 in CRC liver metastases was studied using CRC cell lines. Migration and invasion assays were used to verify tumor cell migratory and invasive capabilities. The relationship between CLDN9 and MHC Class I Antigen Presentation was investigated by Flow Cytometry. Results We obtained the highly metastatic cell line CT26-LM by constructing a colorectal cancer liver metastasis model in immune-competent mice (IDDF2024-ABS-0407 Figure 1. Identification of CLDN9 as a potential therapeutic target for colorectal cancer liver metastasis patients (A, E, F)). Afterward, we discovered that CLDN9 was abnormally overexpressed in CRC tissues and correlated with TNM stage, metastasis, and neural tract infiltration (IDDF2024-ABS-0407 Table 1, IDDF2024-ABS-0407 Figure 1. Identification of CLDN9 as a potential therapeutic target for colorectal cancer liver metastasis patients (H-I)). In vitro and in vivo functional assays showed that CLDN9 enhanced the migration and invasion of colorectal cancer cells (IDDF2024-ABS-0407 Figure 2. Function MHC class antigen presentation (D-F)). In addition, Protein mass spectrometry results demonstrated that the CLDN9-interacting proteins are involved in mediating MHC Class I Antigen Presentation (IDDF2024-ABS-0407 Figure 2. Function MHC class antigen presentation (H)). Flow Cytometry indicated that high expression of CLDN9 inhibits MHC Class I Antigen Presentation (IDDF2024-ABS-0407 Figure 2. Function MHC class antigen presentation (I)). Conclusions Our preliminary data suggest that high expression of CLDN9 leads to tumor immune evasion through inhibiting MHC Class I Antigen Presentation, thereby promoting colorectal cancer liver metastasis. Targeting CLDN9 presents a promising therapeutic strategy for the treatment of CRC liver metastases.