Intrinsic β-catenin signaling suppresses CD8+ T-cell infiltration in colorectal cancer

Abstract

Colorectal cancer is the third most common cancer worldwide and shows resistance to immune checkpoint inhibitors which have been demonstrated to be effective in many other types of cancers. Pre-existing T-cell response in tumor microenvironment often determines the therapeutic benefit of immune checkpoint blockade. Tumor-infiltrating CD8+ T-cells are considered as the major effector immune cells in antitumor immunity. In this study, we aimed to identify the intrinsic oncogenic pathway that contributes to a reduction of CD8+ T-cell infiltration in colorectal cancer. To achieve this, human colon adenocarcinoma samples derived from The Cancer Genome Altas (TCGA) were stratified into low T-cell-inflamed and high T-cell-inflamed groups based on the expression of T-cell signature genes. Gene set enrichment analysis of revealed a close correlation between activation of the Wnt/β-catenin signaling pathway and absence of T-cell infiltration. By immunohistochemical analysis of 155 colorectal cancer tissues, we found that tumors with high β-catenin expression showed a significant reduction of CD8+ T-cell infiltration. Mechanistically, β-catenin can regulate CCL4 expression to recruit CD103+ dendritic cells to enable CD8+ T cell activation. Collectively, our data indicate that oncogenic β-catenin signal may mediate colorectal cancer resistance to immunotherapies, pointing to the combined PD-1-immunotherapy with targeting β-catenin in colorectal cancer.