YTHDF1 loss in dendritic cells potentiates radiation-induced antitumor immunity via STING-dependent type I IFN production
The RNA N6-methyladenosine (m6A) reader YTHDF1 is implicated in cancer etiology and progression. We discovered that radiotherapy (RT) increased YTHDF1 expression in dendritic cells (DCs) of PBMCs from patients with cancer, but not in other immune cells tested. Elevated YTHDF1 expression in DCs was associated with poor outcomes for patients receiving RT. We found that loss of Ythdf1 in DCs enhanced the antitumor effects of ionizing radiation (IR) by increasing the cross-priming capacity of DCs across multiple murine cancer models. Mechanistically, IR upregulated YTHDF1 expression in DCs through stimulator of IFN genes/type I IFN (STING/IFN-I) signaling. YTHDF1 in turn triggered STING degradation by increasing lysosomal cathepsins, thereby reducing IFN-I production. We created a YTHDF1 deletion/inhibition prototype DC vaccine that significantly improved the therapeutic effect of RT and radioimmunotherapy in a murine melanoma model. Our findings reveal a layer of regulation between YTHDF1/m6A and STING in response to IR, which opens new paths for the development of YTHDF1-targeting therapies.
Authors
- Xiaona Huang (ORCID: https://orcid.org/0000-0002-9983-5723)
- Stephen Y. Luo (ORCID: https://orcid.org/0009-0009-2608-5544)
- Chuangyu Wen (ORCID: https://orcid.org/0000-0002-4416-116X)
- Katarzyna Zawieracz
- Xianbin Yu (ORCID: https://orcid.org/0000-0002-7508-8006)
- Cheng Luo (ORCID: https://orcid.org/0000-0003-3864-8382)
- András Piffkó (ORCID: https://orcid.org/0000-0001-5300-6594)
- Sean P. Pitroda (ORCID: https://orcid.org/0000-0003-3056-7991)
- Fei Ji (ORCID: https://orcid.org/0000-0002-6890-4933)
- Megan E. McNerney (ORCID: https://orcid.org/0000-0002-8260-3598)
- Jason Bugno (ORCID: https://orcid.org/0000-0002-3046-8072)
- Bin Shen (ORCID: https://orcid.org/0000-0002-8946-8448)
- Kaiting Yang (ORCID: https://orcid.org/0000-0001-9328-5655)
- Ralph R. Weichselbaum (ORCID: https://orcid.org/0000-0002-5643-8939)
- Ainhoa Arina (ORCID: https://orcid.org/0000-0002-0585-7148)
- Steven J. Chmura (ORCID: https://orcid.org/0000-0001-8851-7108)
- Lei Tan (ORCID: https://orcid.org/0000-0002-9358-4898)
- Jiaai Wang (ORCID: https://orcid.org/0000-0003-3217-7444)
- Emile Naccasha (ORCID: https://orcid.org/0009-0005-5445-9313)
- Liangliang Wang (ORCID: https://orcid.org/0000-0001-8340-5190)
- Dapeng Chen (ORCID: https://orcid.org/0000-0001-8109-8879)
- Chuan He
- Hua Liang (ORCID: https://orcid.org/0000-0001-5512-8595)
Institutions
- Northwestern University (US)
- NorthShore University HealthSystem (US)
- Howard Hughes Medical Institute (US)
- Universität Hamburg (DE)
- Chinese Academy of Sciences (CN)
- University of Chicago (US)
- Nanjing Maternity and Child Health Care Hospital (CN)
- University Medical Center Hamburg-Eppendorf (DE)
- Shanghai Institute of Materia Medica (CN)
- Max Planck Institute for Biophysical Chemistry (DE)
- Institute of Microbiology (CN)
- Nanjing Medical University (CN)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2024-09-26
- DOI
- https://doi.org/10.1172/jci181612
- Citations
- 20
- Primary Topic
- interferon and immune responses
- Type
- article
- Field-Weighted Citation Impact
- 4.81
Funders
- AstraZeneca
- University of Chicago
- Ludwig Institute for Cancer Research
- Regeneron Pharmaceuticals
- Deutsche Forschungsgemeinschaft
- National Institutes of Health
- National Cancer Institute