USP22 drives tumor immune evasion and checkpoint blockade resistance through EZH2-mediated epigenetic silencing of MHC-I
Kun Liu, Radhika Iyer, Yi Li, Jun Zhu, Zhaomeng Cai, Juncheng Wei, Yang Cheng, Amy Y. Tang, Hai Wang, Qiong Gao, Nikita Lavanya Mani, Noah Marx, Beixue Gao, D. Martin Watterson, Seema A. Khan, William J. Gradishar, Huiping Liu, Deyu Fang
Kun Liu, Radhika Iyer, Yi Li, Jun Zhu, Zhaomeng Cai, Juncheng Wei, Yang Cheng, Amy Y. Tang, Hai Wang, Qiong Gao, Nikita Lavanya Mani, Noah Marx, Beixue Gao, D. Martin Watterson, Seema A. Khan, William J. Gradishar, Huiping Liu, Deyu Fang
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Research Article Clinical Research Immunology Oncology

USP22 drives tumor immune evasion and checkpoint blockade resistance through EZH2-mediated epigenetic silencing of MHC-I

Abstract

While immune checkpoint blockade (ICB) therapy has revolutionized the antitumor therapeutic landscape, it remains successful in only a small subset of patients with cancer. Poor or loss of MHC-I expression has been implicated as a common mechanism of ICB resistance. Yet, the molecular mechanisms underlying impaired MHC-I remain to be fully elucidated. Herein, we identified USP22 as a critical factor responsible for ICB resistance through suppressing MHC-I–mediated neoantigen presentation to CD8+ T cells. Both genetic and pharmacologic USP22 inhibition increased immunogenicity and overcame anti–PD-1 immunotherapeutic resistance. At the molecular level, USP22 functions as a deubiquitinase for the methyltransferase EZH2, leading to transcriptional silencing of MHC-I gene expression. Targeted Usp22 inhibition resulted in increased tumoral MHC-I expression and consequently enhanced CD8+ T cell killing, which was largely abrogated by Ezh2 reconstitution. Multiplexed immunofluorescence staining detected a strong reverse correlation between USP22 expression and both β2M expression and CD8+ T lymphocyte infiltration in solid tumors. Importantly, USP22 upregulation was associated with ICB immunotherapeutic resistance in patients with lung cancer. Collectively, this study highlights the role of USP22 as a diagnostic biomarker for ICB resistance and provides a potential therapeutic avenue to overcome the current ICB resistance through inhibition of USP22.

Authors

Kun Liu, Radhika Iyer, Yi Li, Jun Zhu, Zhaomeng Cai, Juncheng Wei, Yang Cheng, Amy Y. Tang, Hai Wang, Qiong Gao, Nikita Lavanya Mani, Noah Marx, Beixue Gao, D. Martin Watterson, Seema A. Khan, William J. Gradishar, Huiping Liu, Deyu Fang

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Figure 7

Targeting USP22 overcomes ICB resistance.

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Targeting USP22 overcomes ICB resistance. (A and B) Effects of administr...
(A and B) Effects of administration of anti-PD–1 on 4T1 or 4T1R tumor growth (A) and weight (B). Scale bar: 1 cm. Image of 4T1 or 4T1 R tumors treated with or without anti-PD–1 are shown. (C and D) Effects of Usp22 deficiency on 4T1 or 4T1R tumor growth (C) and weight (D). (E and F) Effects of S02 or anti-PD–1 in 4T-1 R tumor growth. Mice were randomly grouped into 4 groups and administered with 10 mg/kg USP22i-S02 and/or 100 mg anti-PD–1. Mice were treated with 10 mg/kg S02 daily from day 4 to day 9, or were given a combination treatment with 100 μg anti-PD-1 antibodies every other day from day 4 to day 8. (G–I) Representative flow cytometric images and quantification data of cell surface b2M (G), H-2Kd (H), or PD-L1 (I) MFI in indicated tumor cells. (J) Representative flow cytometric images and quantification of FoxP3 MFI. (K) Representative images of flow cytometric analysis and quantification of frequencies of Tregs among total CD4+ lymphocytes in indicated tumors. (L) Quantification of frequencies of CD8+ T cells among tumor-infiltrating CD45+ lymphocytes in indicated tumors. (M and N) Representative flow cytometric images and quantification of frequencies of GZMB- (M) or IFN-γ– (N) producing tumor-infiltrating CD8+ T cells in indicated tumors. (O) Proposed working model showing that USP22 inhibition enhances antitumor immunity through increases in EZH2 proteasomal mediated degradation and MHC-I mediated. CD8+ T cells recognition and killing. Pharmacological USP22 inhibition overcomes immune checkpoint blockade resistance. Statistics were calculated by 1-way ANOVA followed by Tukey’s test (B, D, and F–N) or 2-way ANOVA with multiple comparisons (A, C, and E). *P < 0.05, **P < 0.01, and ***P < 0.001.