2. Academic Validation
  3. YTHDF2 inhibition potentiates radiotherapy antitumor efficacy

YTHDF2 inhibition potentiates radiotherapy antitumor efficacy

  • Cancer Cell. 2023 May 15;S1535-6108(23)00163-0. doi: 10.1016/j.ccell.2023.04.019.
Liangliang Wang 1,  Xiaoyang Dou 2,  Shijie Chen 3,  Xianbin Yu 2,  Xiaona Huang 1,  Linda Zhang 2,  Yantao Chen 3,  Jiaai Wang 1,  Kaiting Yang 1,  Jason Bugno 4,  Sean Pitroda 1,  Xingchen Ding 5,  Andras Piffko 6,  Wei Si 7,  Chao Chen 3,  Hualiang Jiang 3,  Bing Zhou 3,  Steven J Chmura 8,  Cheng Luo 9,  Hua Laura Liang 10,  Chuan He 11,  Ralph R Weichselbaum 12
Affiliations

Affiliations

  • 1 Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL 60637, USA; Ludwig Center for Metastasis Research, University of Chicago, Chicago, IL 60637, USA.
  • 2 Department of Chemistry, Department of Biochemistry and Molecular Biology, and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637, USA; Howard Hughes Medical Institute, University of Chicago, Chicago, IL 60637, USA.
  • 3 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 4 Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL 60637, USA; Ludwig Center for Metastasis Research, University of Chicago, Chicago, IL 60637, USA; The Committee on Clinical Pharmacology and Pharmacogenomics, University of Chicago, Chicago, IL 600637, USA.
  • 5 Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, China.
  • 6 Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL 60637, USA; Ludwig Center for Metastasis Research, University of Chicago, Chicago, IL 60637, USA; Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.
  • 7 State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China.
  • 8 Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL 60637, USA.
  • 9 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528437, China. Electronic address: cluo@simm.ac.cn.
  • 10 Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL 60637, USA; Ludwig Center for Metastasis Research, University of Chicago, Chicago, IL 60637, USA. Electronic address: hualiang@uchicago.edu.
  • 11 Department of Chemistry, Department of Biochemistry and Molecular Biology, and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637, USA; Howard Hughes Medical Institute, University of Chicago, Chicago, IL 60637, USA; Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL 60637, USA. Electronic address: chuanhe@uchicago.edu.
  • 12 Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL 60637, USA; Ludwig Center for Metastasis Research, University of Chicago, Chicago, IL 60637, USA. Electronic address: rweichselbaum@bsd.uchicago.edu.
PMID: 37236197 DOI: 10.1016/j.ccell.2023.04.019
Abstract

RNA N6-methyladenosine (m6A) modification is implicated in Cancer progression. However, the impact of m6A on the antitumor effects of radiotherapy and the related mechanisms are unknown. Here we show that ionizing radiation (IR) induces immunosuppressive myeloid-derived suppressor cell (MDSC) expansion and YTHDF2 expression in both murine models and humans. Following IR, loss of Ythdf2 in myeloid cells augments antitumor immunity and overcomes tumor radioresistance by altering MDSC differentiation and inhibiting MDSC infiltration and suppressive function. The remodeling of the landscape of MDSC populations by local IR is reversed by Ythdf2 deficiency. IR-induced YTHDF2 expression relies on NF-κB signaling; YTHDF2 in turn leads to NF-κB activation by directly binding and degrading transcripts encoding negative regulators of NF-κB signaling, resulting in an IR-YTHDF2-NF-κB circuit. Pharmacological inhibition of YTHDF2 overcomes MDSC-induced immunosuppression and improves combined IR and/or anti-PD-L1 treatment. Thus, YTHDF2 is a promising target to improve radiotherapy (RT) and RT/immunotherapy combinations.

Keywords

MDSCs; NF-kB; Radiation; YTHDF2; m6A.

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