YTHDF2 upregulation and subcellular localization dictate CD8 T cell polyfunctionality in anti-tumor immunity

Haiyan Zhang, Xiaojing Luo, Wei Yang, Zhiying Wu, Zhicong Zhao, Xin Pei, Xue Zhang, Chonghao Chen, Josh Haipeng Lei, Qingxia Shi, Qi Zhao, Yanxing Chen, Wenwei Wu, Zhaolei Zeng, Huai-Qiang Ju, Miaozhen Qiu, Jun Liu, Bin Shen, Minshan Chen, Jianjun Chen, Chu-Xia Deng, Rui-Hua Xu () and Jiajie Hou ()
Additional contact information
Haiyan Zhang: University of Macau
Xiaojing Luo: Sun Yat-sen University Cancer Center
Wei Yang: Sun Yat-sen University Cancer Center
Zhiying Wu: Sun Yat-sen University Cancer Center
Zhicong Zhao: The Beckman Research Institute of City of Hope
Xin Pei: University of Macau
Xue Zhang: University of Macau
Chonghao Chen: University of Macau
Josh Haipeng Lei: University of Macau
Qingxia Shi: University of Macau
Qi Zhao: Sun Yat-sen University Cancer Center
Yanxing Chen: Sun Yat-sen University Cancer Center
Wenwei Wu: Sun Yat-sen University Cancer Center
Zhaolei Zeng: Sun Yat-sen University Cancer Center
Huai-Qiang Ju: Sun Yat-sen University Cancer Center
Miaozhen Qiu: Sun Yat-sen University Cancer Center
Jun Liu: Peking University
Bin Shen: Nanjing Medical University
Minshan Chen: Sun Yat-sen University Cancer Center
Jianjun Chen: The Beckman Research Institute of City of Hope
Chu-Xia Deng: University of Macau
Rui-Hua Xu: Sun Yat-sen University Cancer Center
Jiajie Hou: University of Macau

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract RNA methylation is an important regulatory process to determine immune cell function but how it affects the anti-tumor activity of CD8 T cells is not fully understood. Here we show that the N6-methyladenosine (m6A) RNA reader YTHDF2 is highly expressed in early effector or effector-like CD8 T cells. We find that YTHDF2 facilitates nascent RNA synthesis, and m6A recognition is fundamental for this distinctively nuclear function of the protein, which also reinforces its autoregulation at the RNA level. Loss of YTHDF2 in T cells exacerbates tumor progression and confers unresponsiveness to PD-1 blockade in mice and in humans. In addition to initiating RNA decay that is necessary for mitochondrial fitness, YTHDF2 orchestrates chromatin changes that promote T cell polyfunctionality. YTHDF2 interacts with IKZF1/3, which is important for sustained transcription of their target genes. Accordingly, immunotherapy-induced efficacy could be largely restored in YTHDF2-deficient T cells through combinational use of IKZF1/3 inhibitor lenalidomide in a mouse model. Thus, YTHDF2 coordinates epi-transcriptional and transcriptional networks to potentiate T cell immunity, which could inform therapeutic intervention.

Date: 2024
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DOI: 10.1038/s41467-024-53997-6

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