Tet2 at the interface between cancer and immunity

Abstract

Keeping a balance between DNA methylation and demethylation balance is central for mammalian development and cell function, particularly in the hematopoietic system. In various mammalian cells, Tet methylcytosine dioxygenase 2 (Tet2) catalyzes oxygen transfer to a methyl group of 5-methylcytosine (5mC), yielding 5-hydroxymethylcytocine (5hmC). Tet2 mutations drive tumorigenesis in several blood cancers as well as in solid cancers. Here I discuss recent studies that elucidate mechanisms and biological consequences of Tet2 dysregulation in blood cancers. I focus on recent findings concerning Tet2 involvement in lymphoid and myeloid cell development and its functional roles, which may be associated with tumorigenesis. I also discuss how Tet2 activities are modulated by microRNAs, metabolites, and other interactors, including vitamin C and 2-hydroxyglutarate (2-HG), and review the clinical relevance and potential therapeutic applications of Tet2 targeting. Finally, I propose key unanswered hypotheses regarding Tet2 in the cancer-immunity cycle.

Fig. 1. Tet2 in the cancer-immunity crosstalk.

Tet2 loss causes an accumulation of 5mC, which promotes B-cell development and B-cell function. Tet2 loss also promotes CD4⁺ T-cell differentiation and M1 macrophage responses, which can modulate cancer cell activities. In contrast, cancer cells that carry Tet2 mutations counteract positive immune-cell responses, including T-cell and macrophages.

Fig. 2. Potential therapeutic strategies related to cancer-immunity, based on interactors, specifically targeting Tet2 activities in immune and cancer cells.

The Tet2 activities might be enhanced by vitamin C and hypoxia treatment through HIF-1a. The Tet2 activities might be halted by blocking a-KG accumulation, selective OGT inhibition, selective IDH2 inhibition, using anti-Fe²⁺ agent, or directly suppressed by microRNAs (e.g., Let-7 and miR-22), Tet2 shRNA lentivirus, and Crispr/cas9 targeting in cancer and immune cells.