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 4

USP22 attenuates antitumor immunity partially through protecting EZH2 from degradation.

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USP22 attenuates antitumor immunity partially through protecting EZH2 fr...
(A–C) Indicated cancer cells were treated with 10 ng/mL IFN-γ for indicated time points. The expression of indicated proteins was determined. (D) HEK-293T cells were cotransfected with FLAG-EZH2 and Myc-USP22 and then treated with 10 ng/mL IFN-γ for the indicated times. The interaction between USP22 and EZH2 was determined. (E) Tumor cells were isolated based on membrane b2M expression. Indicated protein expression was determined. (F) MC38/OVA or RM1/OVA were isolated according to cell surface pMHC-I. Indicated protein expression was determined. (G) OT-I CD8+ T cells were isolated from OT-I mice and cocultured with Usp22-deficient RM1/OVA or MC38/OVA cells with or without Ezh2, Ezh2 F667I, or ΔSET mutant reconstitution for 8 hours at the ratio of 1:1 in the presence of CD28 blocking antibodies treatment. Quantification data of flow cytometric analysis of percentages of GZMB+, IFN-γ+, and TNF-α+ producing CD8+ T cells are shown. (H) Cell viability of indicated cells after coculturing for 48 hours. (I) Living tumor cells were collected after coculture with naive OT-I CD8+ T cells for 48 hours at a ratio of 1:1 in the presence of CD28 blocking antibody treatment. Indicated protein levels were determined. (J and K) MC38 cells with Ezh2, Ezh2 F667I, or ΔSET mutant reconstitution in the setting of Usp22 depletion were inoculated into immunocompetent mice. Tumor volume (J) and endpoint mass (K) of indicated tumors were recorded. (L) The expression of b2M and H-2Kb on indicated tumor cell surface. (M and N) The frequencies of tumoral-infiltrating CD8+ T cells (M) or GZMB+ producing CD8+ T cells (N) from indicated MC38 tumors. Statistics were calculated by 1-way ANOVA followed by Tukey’s test (G, H, and K–N). Two-way ANOVA with multiple comparisons (C and J). *P < 0.05, **P < 0.01, and ***P < 0.001.