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 2

Ythdf1 deficiency increases the cross-priming capacity of DCs in the context of IR.

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Ythdf1 deficiency increases the cross-priming capacity of DCs in the co...
(A and B) WT and Ythdf1-cKO mice were injected s.c. with B16-OZ cells. Tumor-bearing mice were treated with local IR (20 Gy, 1 dose) when tumor volumes reached 100–200 mm3. On day 5 after IR, CD11c+ cells from TDLNs were isolated and cocultured with OT-I T cells for 3 days, and then IFN-γ–producing cells were enumerated by ELISPOT (n = 5) (A); in tumor-infiltrating DCs (CD45+F4/80–CD11c+MHC-II+), the formation of H-2Kb-SIINFEKL was detected by flow cytometry (n = 5) (B). (C–E). On day 8 after IR, the proportions of CD8+ T cells (CD45+CD3+CD8+) (C), IFN-γ (D), and granzyme B (E) in CD8+ T cells were detected by flow cytometry (n = 5). (F) On day 8 after IR, CD8+ T cells were isolated from TDLNs. Tumor antigen–specific CD8+ T cell function was measured via ELISPOT by coculturing CD8+ T cells with 5 μg/mL OT-I peptide (n = 5). (G) A dose of 200 μg anti-CD8 mAb was delivered twice weekly by i.p. injection to deplete CD8+ T cells, starting 1 day before IR. Tumor growth was monitored after IR. (H) Proposed model of how Ythdf1 KO in DCs sensitizes a tumor to IR by increasing the antitumor activity of CD8+ T cells. Data are presented as the mean ± SEM. Data are representative of 2 or 3 independent experiments. One-way ANOVA with Tukey’s multiple-comparison test (A–F) and 2-way ANOVA with Tukey’s multiple-comparison test (G). *P < 0.05, **P < 0.01, and ***P < 0.001.