Molecular Underpinnings and Significance of Regulatory T-cell Plasticity in Cancer

Abstract Text: Regulatory T-cells (Treg cells) are endowed with functional plasticity which facilitates their response to changes in environmental stimuli and tissue homeostasis. This plasticity becomes a liability in chronic inflammatory diseases such as in cancer. We found that Tregs isolated from colorectal cancer patients have enhanced T-cell suppressive properties but are compromised in suppressing inflammation. These changes correlated with elevated levels of -catenin. We used genetic mouse models to show that stabilization of b-catenin or loss of its DNA binding partner TCF-1 causes the activation of Tregs but compromises their ability to suppress inflammation. TCF-1 suppressed the transcription of genes that were co-bound by Foxp3. Single-cell RNA-sequencing analysis identified clusters of Treg cells with differential expression of memory and activation markers. TCF-1 deficiency did not change the core Treg cell transcriptional signature but promoted alternative signaling pathways whereby Treg cells became activated and gained gut-homing, T-cell suppressive, and TH17 characteristics. TCF-1-deficient Treg cells strongly suppressed T cell proliferation and cytotoxicity but were compromised in controlling CD4+ T cell polarization and inflammation. In mice with polyposis, Treg cell–specific TCF-1 deficiency enhanced tumor growth. Consistently, tumor-infiltrating Treg cells of patients with colorectal cancer showed lower TCF-1 expression and increased TH17 expression signatures compared to adjacent normal tissue and circulating T cells. Thus, b-catenin/TCF-1 regulate Treg plasticity in colorectal cancer to promote pathogenic TH17 inflammation and suppress tumor-directed T cell cytotoxicity. These changes can determine colorectal cancer outcomes.

This work was supported by National Institutes of Health (NIH) grants R01 AI 108682 and R01CA160436.