YTHDF2/m6A/NF‐κB axis controls anti‐tumor immunity by regulating intratumoral Tregs

• Published in: The EMBO journal Vol. 42; no. 15
• Main Authors: Zhang, Linda, Dou, Xiaoyang, Zheng, Zhong, Ye, Chang, Lu, Thomas X, Liang, Hua L, Wang, Liangliang, Weichselbaum, Ralph R, He, Chuan
• Format: Journal Article
• Language: English
• Published: Heidelberg Blackwell Publishing Ltd 01.08.2023; John Wiley and Sons Inc
• Subjects: Anti‐tumor immunity; Apoptosis; Cancer immunotherapy; Deletion; Homeostasis; Immune response; Immune system; Immunotherapy; Infiltration capacity; Intratumoral Tregs; Lymphocytes T; m6A; Metastases; N6-methyladenosine; NF‐κB regulation; Tumor microenvironment; Tumor necrosis factor; Tumor necrosis factor-TNF; Tumors; YTHDF2
• ISSN: 0261-4189; 1460-2075
• DOI: 10.15252/embj.2022113126

N6‐methyladenosine (m6A) in messenger RNA (mRNA) regulates immune cells in homeostasis and in response to infection and inflammation. The function of the m6A reader YTHDF2 in the tumor microenvironment (TME) in these contexts has not been explored. We discovered that the loss of YTHDF2 in regulatory T (Treg) cells reduces tumor growth in mice. Deletion of Ythdf2 in Tregs does not affect peripheral immune homeostasis but leads to increased apoptosis and impaired suppressive function of Treg cells in the TME. Elevated tumor necrosis factor (TNF) signaling in the TME promotes YTHDF2 expression, which in turn regulates NF‐κB signaling by accelerating the degradation of m6A‐modified transcripts that encode NF‐κB‐negative regulators. This TME‐specific regulation of Treg by YTHDF2 points to YTHDF2 as a potential target for anti‐cancer immunotherapy, where intratumoral Treg cells can be targeted to enhance anti‐tumor immune response while avoiding Treg cells in the periphery to minimize undesired inflammations. Synopsis The RNA m6A‐binding protein YTHDF2 regulates NF‐κB signaling to maintain intratumoral Treg survival and function. Deletion of Ythdf2 in Treg cells delays tumor development in mice while maintaining peripheral homeostasis. Ythdf2‐deficient Treg cells have reduced infiltration capacity and impaired function. TNF/NF‐κB signaling elevates the expression of YTHDF2. YTHDF2 accelerates the decay of m6A‐modified transcripts encoding NF‐κB‐negative regulators. The m6A reader YTHDF2 promotes tumor growth via regulation of Treg function and NF‐κB signaling.