YTHDF2 upregulation and relocation dictate CD8 T cell polyfunctionality in tumor immunity
Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
Epigenetic traits impact the antitumor function of CD8 T cells, yet whether and how RNA methylation programs engage in T cell immunity is poorly understood. Here we show that the N 6 -methyladenosine (m 6 A) RNA reader YTHDF2 is highly expressed in early effector or effector-like CD8 T cells and is partially distributed in the nucleus. YTHDF2 loss in T cells exacerbates tumor progression and confers unresponsiveness to PD-1 blockade in mice and humans. In addition to initiating RNA decay for mitochondrial fitness, YTHDF2 can orchestrate chromatin regulation to promote T cell polyfunctionality. YTHDF2-mediatd preservation of gene transcription arises from the interaction of YTHDF2 with IKZF1/3. Accordingly, immunotherapy-induced efficacy could be largely restored in YTHDF2-deficient T cells through combinational use of lenalidomide. Moreover, m 6 A recognition is fundamental for YTHDF2 translocation to the nucleus and autoregulation at the RNA level. Thus, YTHDF2 coordinates epitranscriptional and transcriptional networks to potentiate T cell immunity.
Highlights
-
YTHDF2 expression and distribution underpin the threshold for bona fide CD8 T cell effector response
-
Canonical YTHDF2-mRNA decay pathway alleviates mitochondrial stress and CD8 T cell exhaustion
-
Nuclear YTHDF2 sequesters IKZF1/3-mediated transcriptional repression to safeguard CD8 T cell polyfunctionality
-
The tumoricidal activity of YTHDF2-deficient CD8 T cells could be repaired through the synergy of anti-PD-1 and lenalidomide
