Wnt Signaling as a Modulator of T_reg Activity in Colorectal Cancer

The morbidity and mortality of colorectal cancer (CRC) remain high, even with well-established detection and treatment programs. A major factor in the development of CRC is the uncontrolled activation of the Wnt signaling pathway which leads to expression of genes that affect cell proliferation, cell polarity and cell fate – all crucial for cancer development. Unfortunately, the success of cancer immunotherapy as a treatment for CRC is currently very limited. Regulatory T Cells (T_regs) are CD4⁺CD25^highFoxp3⁺ cells that normally function as keepers of self-tolerance. At the tumor microenvironment of CRC, T_regs are abundant and potent, hindering the immune system and possibly inhibiting immunotherapies.

Although Wnt signaling and T_reg infiltration are both extensively studied in CRC, the connection between them is unknown and we are currently studying the activity of the Wnt cascade in T_regs aiming at identifying novel T_reg inhibitors.

Starting with human whole blood, we have isolated CD4⁺CD25^high cells. Next, by RT-qPCR analysis, we have ascertained a phenotype consistent with T_regs using markers such as Foxp3 and CD127. Currently, we are characterizing the expression of Wnt-related genes in these cells. Using a specific Wnt gene expression microarray we will identify up- or down- regulated genes of the Wnt pathway in T_regs.

Ultimately, comparison between healthy and CRC-infiltrating T_regs may allow us to identify novel targets to alleviate the suppressive phenotype of tumor-infiltrating T_regs and possibly uncovering a synergistic effect with existing immunotherapies.