Posttranscriptional regulation of PD-1 by PRMT5/WDR77 complex shapes T cell effector function and antitumor immunity
Yinmin Gu, Yongbo Pan, Chang Pan, Qiang Pang, Zhantong Tang, Yiwen Chen, Haojing Zang, Xiaodong Wang, Chang Huang, Qingqing Zhang, Facai Yang, Xiaofeng Zhu, Yibi Zhang, Xujie Zhao, Shan Gao
Yinmin Gu, Yongbo Pan, Chang Pan, Qiang Pang, Zhantong Tang, Yiwen Chen, Haojing Zang, Xiaodong Wang, Chang Huang, Qingqing Zhang, Facai Yang, Xiaofeng Zhu, Yibi Zhang, Xujie Zhao, Shan Gao
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Research Article Genetics Immunology

Posttranscriptional regulation of PD-1 by PRMT5/WDR77 complex shapes T cell effector function and antitumor immunity

Abstract

The regulation of the programmed cell death protein 1 (PD-1) gene, PDCD1, has been widely explored at transcription and posttranslational levels in T cell function and tumor immune evasion. However, the mechanism for PDCD1 dysregulation at the posttranscriptional level remains largely unknown. Here, we identify protein arginine methyltransferase 5 (PRMT5) as a RNA binding protein in a methyltransferase activity–independent manner, which promotes PDCD1 decay with WD repeat domain 77 protein (WDR77) and Argonaute2. Furthermore, the type-I IFN/STAT1 pathway transcriptionally activates PRMT5 and WDR77, thus enhancing PRMT5/WDR77 binding on a conserved AU-rich element of PDCD1 3′ UTR. Functionally, conditional knockout of either PRMT5 or WDR77 in T cells disrupts T cell effector function and sensitizes the tumors to anti–PD-1 therapy. Clinically, PRMT5 and WDR77 expression in tumor-infiltrating T cells are negatively correlated with PDCD1 expression and renders tumors resistant to PD-1–targeted immunotherapy. Moreover, fludarabine targeting STAT1 in combination with anti–PD-1 has a synergetic effect on suppressing tumor growth in mice. Overall, this study reveals that the RNA binding–dependent function of PRMT5 regulates PDCD1 and T cell effector function with WDR77 and identifies potential combinatorial therapeutic strategies for enhancing antitumor efficacy.

Authors

Yinmin Gu, Yongbo Pan, Chang Pan, Qiang Pang, Zhantong Tang, Yiwen Chen, Haojing Zang, Xiaodong Wang, Chang Huang, Qingqing Zhang, Facai Yang, Xiaofeng Zhu, Yibi Zhang, Xujie Zhao, Shan Gao

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Figure 6

The type I IFN/STAT1 pathway decreases PD-1 expression through activation of PRMT5 and WDR77 transcriptionally.

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The type I IFN/STAT1 pathway decreases PD-1 expression through activatio...
(A and B) The relative mRNA levels of PRMT5 and WDR77 in STAT1 KD (A) and OE (B) Jurkat cells. (C) Immunoblotting of PRMT5 and WDR77 expression in STAT1 KD (left) and OE (right) Jurkat cells. (D–G) The relative mRNA levels (D and F) and protein (E and G) levels of PRMT5 and WDR77 in Jurkat cells treated with IFN-α or IFN-β. (H and I) ChIP-qPCR analysis of PRMT5 (H) or WDR77 (I) promoter enriched by STAT1 in Jurkat cells treated with IFN-α or IFN-β. (J) RIP-qPCR analysis of PDCD1 3′ UTR enriched by PRMT5 or WDR77 in Jurkat cells treated with IFN-α or IFN-β. (K and L) Representative flow cytometry plots (K) and quantification (L) of in vitro killing of MC38-OVA cells by OT-1 CD8+ T cells with or without fludarabine or anti–PD-1 treatment. (M and N) Tumor growth curves (M) and survival rates (N) were assessed in mice treated with fludarabine and anti–PD-1. (O–V) Endpoint tumor size (O), tumor mass (P), and flow cytometry analysis (Q–V) showing the percentage of CD8+ T cells in CD3+ T cells (S), the percentage of PRMT5+ (Q), PD-1+ (R), IFN-γ+ (T), TNF-α+ (U),and Gzmb+ (V) in CD8+ T cell populations of subcutaneous MC38 tumors from mice treated with fludarabine and anti–PD-1. For A, D, F, and H–J (n = 3), by 1-way ANOVA with Dunnett’s test; for B (n = 3), by unpaired 2-tailed Student’s t test; For L (n = 4,) M (n = 8), and P–V (n = 5), by 2-way ANOVA. Data are presented as mean ± SEM or SD. *P < 0.05, **P < 0.01, ***P < 0.001.