YTHDF2 upregulation and subcellular localization dictate CD8 T cell polyfunctionality in anti-tumor immunity
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 N<sup>6</sup>-methyladenosine (m<sup>6</sup>A) RNA reader YTHDF2 is highly expressed in early effector or effector-like CD8 T cells. We find that YTHDF2 facilitates nascent RNA synthesis, and m<sup>6</sup>A 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.
Authors
- Qingxia Shi
- Zhao-Lei Zeng (ORCID: https://orcid.org/0000-0003-4420-5625)
- Bin Shen (ORCID: https://orcid.org/0000-0002-8946-8448)
- Huai‐Qiang Ju (ORCID: https://orcid.org/0000-0003-1713-5465)
- Chu‐Xia Deng (ORCID: https://orcid.org/0000-0001-8033-3902)
- Chonghao Chen (ORCID: https://orcid.org/0000-0003-3919-8598)
- Josh Haipeng Lei (ORCID: https://orcid.org/0000-0002-2058-8054)
- Xiao-Jing Luo (ORCID: https://orcid.org/0000-0001-9440-9189)
- Jiajie Hou (ORCID: https://orcid.org/0000-0002-9011-6837)
- Yanxing Chen (ORCID: https://orcid.org/0000-0002-8571-2802)
- Miao‐Zhen Qiu (ORCID: https://orcid.org/0000-0002-4774-6235)
- Wenwei Wu
- Haiyan Zhang (ORCID: https://orcid.org/0009-0002-6401-7090)
- Jun Liu (ORCID: https://orcid.org/0000-0002-9663-3317)
- Jianjun Chen (ORCID: https://orcid.org/0000-0003-3749-2902)
- Xue Zhang (ORCID: https://orcid.org/0000-0001-7593-6717)
- Xin Pei (ORCID: https://orcid.org/0000-0003-3807-2264)
- Zhiying Wu
- Rui‐Hua Xu (ORCID: https://orcid.org/0000-0001-9771-8534)
- Zhicong Zhao (ORCID: https://orcid.org/0000-0002-3225-2494)
- Minshan Chen (ORCID: https://orcid.org/0000-0002-6116-5015)
- Qi Zhao (ORCID: https://orcid.org/0000-0001-8169-0573)
- Wei Yang (ORCID: https://orcid.org/0009-0005-8713-6262)
Institutions
- Sun Yat-sen University (CN)
- Shanghai Jiao Tong University (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Peking University (CN)
- University of Macau (MO)
- Renji Hospital (CN)
- City of Hope (US)
- Sun Yat-sen University Cancer Center (CN)
- Center for Life Sciences (CN)
- Zhuhai Institute of Advanced Technology (CN)
- Beckman Research Institute
- City University of Macau (MO)
- Nanjing Medical University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-11-05
- DOI
- https://doi.org/10.1038/s41467-024-53997-6
- Citations
- 21
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 4.91
Funders
- Harvard University
- Beckman Research Institute, City of Hope
- National Natural Science Foundation of China
- Sun Yat-sen University
- Natural Science Foundation of Guangdong Province
- Jinan University
- Universidade de Macau
- Fundo para o Desenvolvimento das Ciências e da Tecnologia
- Science and Technology Planning Project of Guangdong Province