Implications of TET2 in CAR-T Cell Activity and Target Response to CAR-T Cell Therapy: Lessons Learned from T Cells

Chimeric antigen receptor T (CAR-T) cell therapy is a recent therapeutic addition to the field of oncology, the first one approved as represented by tisagenlecleucel followed shortly by approval of axicabtagene ciloleucel. Because this product is derived from T cells, there are several lessons that can be learned from T-cell biology to better understand CAR-T cells. Thus, in this review we discuss the effects that TET2 can have on T cells, macrophages interacting with T cells, and nonimmune cells. In T cells, TET2 mutations have been frequently shown to be associated with FOXP3 expression reduction and instability, which leads to reduction in T regulatory (Treg) cells and increases in T-helper (Th)1 and Th17 cells. This alteration in T-cell polarization balance leads to both an enhanced antitumor activity and an increased probability of autoimmune diseases. In the case of macrophages, TET2 has a similar role, as its reduced activity is associated with an M1 signature but its overexpression is associated with an M2 signature. In nonimmune cells, the role of TET2 is opposite its role in immune cells. Specifically, the reduction in TET2 activity is associated with a decreased immune response both in malignancies and in autoimmune diseases. In the current review, we discuss the role that TET2 plays in T-cell activity and in nonimmune cells in relation to T cells.