Abstract
Understanding how colorectal cancer escapes from immunosurveillance and immune attack is important for developing novel immunotherapies for colorectal cancer. In this study we evaluated the role of canonical Wnt signaling in the regulation of T cell function in a mouse colorectal cancer model. We found that colorectal cancer cells expressed abundant Wnt ligands, and intratumoral T cells expressed various Frizzled proteins. Meanwhile, both active β-catenin and total β-catenin were elevated in intratumoral T cells. In vitro study indicated that colorectal cancer cells suppressed IFN-γ expression and increased IL-17a expression in activated CD4+ T cells. However, the cytotoxic activity of CD8+ T cells was not altered by colorectal cancer cells. To further evaluate the importance of Wnt signaling for CD4+ T cell-mediated cancer immunity, β-catenin expression was enforced in CD4+ T cells using lentiviral transduction. In an adoptive transfer model, enforced expression of β-catenin in intratumoral CD4+ T cells increased IL-17a expression, enhanced proliferation and inhibited apoptosis of colorectal cancer cells. Taken together, our study disclosed a new mechanism by which colorectal cancer impairs T cell immunity.
Highlights
Colorectal cancer (CRC) is a major worldwide health problem owing to its high prevalence and mortality rates [1]
In this study we evaluated the role of canonical Wnt signaling in the regulation of T cell function in a mouse colorectal cancer model
We firstly identify the expression of Wnt3, Wnt3a, Wnt5a and Wnt10a in several CRC cell lines
Summary
Colorectal cancer (CRC) is a major worldwide health problem owing to its high prevalence and mortality rates [1]. Immune surveillance and responses have been shown to prevent and inhibit the initiation and progression of CRC [2]. Immune escape is still an intriguing problem involved in CRC pathogenesis and metastasis [3]. Tumor antigenspecific T cells can be detected in the blood and bone marrow of 30% to 40% of patients with CRC [5, 6]. CRC patients with more T cell infiltration have better outcomes [4, 7, 8]. TNF-α and IFN-γ are both critical for T cells to protect CRC patients through inhibition of cancer cell proliferation and induction of apoptosis [9,10,11,12,13,14,15,16,17]
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