YTHDF2 缺失增强 Th9 编程和 CAR-Th9 细胞的抗肿瘤疗效

CD4 + T cells differentiate into various subsets, including T helper 1 (Th1), Th2, Th9, Th17 and regulatory T (T reg ) cells, which are essential for immune responses and cancer immunotherapy.

However, the role of RNA N 6 -methyladenosine (m 6 A) modification in this differentiation is unclear.

Here we show that YTHDF2, an important m 6 A reader protein known to destabilize m 6 A-modified mRNA, negatively regulates Th9 cell differentiation. Ablation of Ythdf2 in both mouse and human naive CD4 + T cells promotes Th9 differentiation by stabilizing Gata3 and Smad3 mRNA under interleukin-4 (IL-4) and transforming growth factor β (TGF-β) signaling, respectively.

Ythdf2-deficient Th9 cells produce increased amounts of IL-9 and IL-21, leading to increased tumor infiltration and cytotoxicity by CD8 + T cells and natural killer (NK) cells, thereby improving antitumor activity compared with wild-type Th9 cells.

Moreover, YTHDF2 depletion in CAR-Th9 cells enhances their immune activation, reduces their terminal differentiation and augments their antitumor efficacy. Targeting YTHDF2 is thereby a promising strategy to enhance Th9 and CAR-Th9 cell-based cancer immunotherapies.