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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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 3

IR increases YTHDF1 expression in DCs via STING/IFN-I signaling.

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IR increases YTHDF1 expression in DCs via STING/IFN-I signaling. (A) Vio...
(A) Violin plot showing the expression of Ythdf1 in total DCs from the scRNA-Seq data collected from tumor-infiltrating CD45+ cells of MC38-bearing mice on day 4 after IR. (B–D). WT mice were injected s.c. with B16-OZ cells. Tumor-bearing mice received local IR (20 Gy, 1 dose) when the tumor volume reached 100–200 mm3. Tumor-infiltrating DCs (CD45+F4/80–CD11c+MHC-II+) were sorted for detection of the expression of YTHDF1 on day 5 after IR via qPCR (n = 3) (B) and Western blotting (C). YTHDF1 expression in tumor-infiltrating DCs by intracellular staining and flow cytometry (n = 5) (D). (E and F) B16-OZ tumor–bearing Ifnar1-KO mice (E) and Sting-KO mice (F) received local IR (20 Gy, 1 dose), and the expression of YTHDF1 in tumor-infiltrating DCs was detected via flow cytometry on day 1 after IR (n = 4 or 5). (G and H) B16-OZ tumor–bearing Sting-KO mice (G) and Ifnar1-KO mice (H) were treated with 2 doses of 10 μg 2′3′-cGAMP (i.t.), and the expression of YTHDF1 of tumor-infiltrating DCs was detected by flow cytometry (n = 5). (I) Proposed mechanism of how IR induces YTHDF1 expression in DCs. IR-induced STING/IFN-I signaling increases the expression of YTHDF1 in DCs. Data are presented as the mean ± SEM. Data are representative of 2 or 3 independent experiments (B–H) Wilcoxon Mann-Whitney U test (A), 2-sided, unpaired Student’s t test (B and D), and 1-way ANOVA with Tukey’s multiple-comparison test (E–H). *P < 0.05, **P < 0.01, and ***P < 0.001.