TOX2 coordinates with TET2 to positively regulate central memory differentiation in human CAR T cells

Chimeric antigen receptor (CAR) T cell therapy is used in treating human hematological malignancies, but its efficacy is limited by T cell exhaustion (T(EX)). T(EX) arises at the expense of central memory T cells (T(CM)), which exhibit robust antitumor efficacy. Reduction of the TET2 gene led to increased T(CM) differentiation in a patient with leukemia who experienced a complete remission. We show that loss of TET2 led to increased chromatin accessibility at exhaustion regulators TOX and TOX2, plus increased expression of TOX2. Knockdown of TOX increased the percentage of T(CM). However, unexpectedly, knockdown of TOX2 decreased T(CM) percentage and reduced proliferation. Consistently, a T(CM) gene signature was reduced in the TOX2 knockdown, and TOX2 bound to promoters of numerous T(CM) genes. Our results thus suggest a role for human TOX2, in contrast to exhaustion regulator TOX, as a potentiator of central memory differentiation of CAR T cells, with plausible utility in CAR T cell cancer therapy via modulated TOX2 expression.