YTHDF1 loss in dendritic cells potentiates radiation-induced antitumor immunity via STING-dependent type I IFN production
Chuangyu Wen, … , Hua Laura Liang, Ralph R. Weichselbaum
Chuangyu Wen, … , Hua Laura Liang, Ralph R. Weichselbaum
Published September 26, 2024
Citation Information: J Clin Invest. 2024;134(23):e181612. https://doi.org/10.1172/JCI181612.
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Research Article Immunology Oncology

YTHDF1 loss in dendritic cells potentiates radiation-induced antitumor immunity via STING-dependent type I IFN production

Abstract

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

Chuangyu Wen, Liangliang Wang, András Piffkó, Dapeng Chen, Xianbin Yu, Katarzyna Zawieracz, Jason Bugno, Kaiting Yang, Emile Z. Naccasha, Fei Ji, Jiaai Wang, Xiaona Huang, Stephen Y. Luo, Lei Tan, Bin Shen, Cheng Luo, Megan E. McNerney, Steven J. Chmura, Ainhoa Arina, Sean Pitroda, Chuan He, Hua Laura Liang, Ralph R. Weichselbaum

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Figure 6

DC vaccines with YTHDF1 deletion/inhibition improve the response to RT and immunotherapy in murine cancers.

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DC vaccines with YTHDF1 deletion/inhibition improve the response to RT a...
(A) Schematic diagram of the DC vaccine treatment plan. D, day. (B) WT mice were injected s.c. with B16-OVA cells. When the tumor volume reached 100–200 mm3, tumor-bearing mice were treated with IR (20 Gy, 1 dose) and antigen-pulsed BMDCs from WT or Ythdf1-KO mice (twice weekly by i.t. injection). (C) BMDCs from WT mice were treated with 20 μM SAC for 24 hours, and the expression of cathepsins A and B was detected by Western blotting. (D) BMDCs from WT mice were pretreated with SAC for 24 hours and then cocultured with 40 Gy–pretreated or nonirradiated B16-OZ cells for 8 hours. Purified CD11c+ cells were incubated for another 2 days, and the supernatants were collected to measure IFN-β (n = 3). (E) B16-OVA tumor–bearing mice were treated with IR (20 Gy, 1 dose) and antigen-pulsed BMDCs from WT mice with or without SAC treatment (twice weekly by i.t. injection). (F) B16-OVA tumor–bearing mice were treated with IR (20 Gy, 1 dose), antigen-pulsed BMDCs from Ythdf1-KO mice (twice weekly by i.t. injection), and anti–PD-L1 (twice weekly by i.p. injection). Data are represented as the mean ± SEM and are representative of 2 or 3 independent experiments. One-way ANOVA with Tukey’s multiple-comparison test (D) and 2-way ANOVA with Tukey’s multiple-comparison test (B, E, and F). *P < 0.05 and ***P < 0.001.