Immune activation is essential for the antitumor activity of EZH2 inhibition in urothelial carcinoma

Andrea Piunti; Khyati Meghani; Yanni Yu; A. Gordon Robertson; Joseph R. Podojil; Kimberly A. McLaughlin; Zonghao You; Damiano Fantini; Ming Yi Chiang; Yi Luo; Lu Wang; Nathan Heyen; Jun Qian; Stephen D. Miller; Ali Shilatifard; Joshua J. Meeks

doi:10.1126/sciadv.abo8043

Immune activation is essential for the antitumor activity of EZH2 inhibition in urothelial carcinoma

Andrea Piunti^*, Khyati Meghani, Yanni Yu, A. Gordon Robertson, Joseph R. Podojil, Kimberly A. McLaughlin, Zonghao You, Damiano Fantini, Ming Yi Chiang, Yi Luo, Lu Wang, Nathan Heyen, Jun Qian, Stephen D. Miller, Ali Shilatifard, Joshua J. Meeks^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

19 Scopus citations

Abstract

The long-term survival of patients with advanced urothelial carcinoma (UCa) is limited because of innate resistance to treatment. We identified elevated expression of the histone methyltransferase EZH2 as a hallmark of aggressive UCa and hypothesized that EZH2 inhibition, via a small-molecule catalytic inhibitor, might have antitumor effects in UCa. Here, in a carcinogen-induced mouse bladder cancer model, a reduction in tumor progression and an increase in immune infiltration upon EZH2 inhibition were observed. Treatment of mice with EZH2i causes an increase in MHC class II expression in the urothelium and can activate infiltrating T cells. Unexpectedly, we found that the lack of an intact adaptive immune system completely abolishes the antitumor effects induced by EZH2 catalytic inhibition. These findings show that immune evasion is the only important determinant for the efficacy of EZH2 catalytic inhibition treatment in a UCa model.

Original language	English (US)
Article number	eabo8043
Journal	Science Advances
Volume	8
Issue number	40
DOIs	https://doi.org/10.1126/sciadv.abo8043
State	Published - Oct 2022

Funding

We thank M. Morgan for providing us with the H3.3 WT and H3.3 K27M plasmids. We thank A. Das and A. Glaser for technical expertise. J.J.M. is supported by grants from the VHA BX003692 and BX005599. A.P. was supported by the transition to independence grant K99CA234434.

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UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Piunti, A., Meghani, K., Yu, Y., Gordon Robertson, A., Podojil, J. R., McLaughlin, K. A., You, Z., Fantini, D., Chiang, M. Y., Luo, Y., Wang, L., Heyen, N., Qian, J., Miller, S. D., Shilatifard, A., & Meeks, J. J. (2022). Immune activation is essential for the antitumor activity of EZH2 inhibition in urothelial carcinoma. Science Advances, 8(40), Article eabo8043. https://doi.org/10.1126/sciadv.abo8043

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title = "Immune activation is essential for the antitumor activity of EZH2 inhibition in urothelial carcinoma",

abstract = "The long-term survival of patients with advanced urothelial carcinoma (UCa) is limited because of innate resistance to treatment. We identified elevated expression of the histone methyltransferase EZH2 as a hallmark of aggressive UCa and hypothesized that EZH2 inhibition, via a small-molecule catalytic inhibitor, might have antitumor effects in UCa. Here, in a carcinogen-induced mouse bladder cancer model, a reduction in tumor progression and an increase in immune infiltration upon EZH2 inhibition were observed. Treatment of mice with EZH2i causes an increase in MHC class II expression in the urothelium and can activate infiltrating T cells. Unexpectedly, we found that the lack of an intact adaptive immune system completely abolishes the antitumor effects induced by EZH2 catalytic inhibition. These findings show that immune evasion is the only important determinant for the efficacy of EZH2 catalytic inhibition treatment in a UCa model.",

author = "Andrea Piunti and Khyati Meghani and Yanni Yu and {Gordon Robertson}, A. and Podojil, {Joseph R.} and McLaughlin, {Kimberly A.} and Zonghao You and Damiano Fantini and Chiang, {Ming Yi} and Yi Luo and Lu Wang and Nathan Heyen and Jun Qian and Miller, {Stephen D.} and Ali Shilatifard and Meeks, {Joshua J.}",

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month = oct,

doi = "10.1126/sciadv.abo8043",

language = "English (US)",

volume = "8",

journal = "Science Advances",

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Piunti, A, Meghani, K, Yu, Y, Gordon Robertson, A, Podojil, JR, McLaughlin, KA, You, Z, Fantini, D, Chiang, MY, Luo, Y, Wang, L, Heyen, N, Qian, J, Miller, SD , Shilatifard, A & Meeks, JJ 2022, 'Immune activation is essential for the antitumor activity of EZH2 inhibition in urothelial carcinoma', Science Advances, vol. 8, no. 40, eabo8043. https://doi.org/10.1126/sciadv.abo8043

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AU - Yu, Yanni

AU - Gordon Robertson, A.

AU - Podojil, Joseph R.

AU - McLaughlin, Kimberly A.

AU - You, Zonghao

AU - Fantini, Damiano

AU - Chiang, Ming Yi

AU - Luo, Yi

AU - Wang, Lu

AU - Heyen, Nathan

AU - Qian, Jun

AU - Miller, Stephen D.

AU - Shilatifard, Ali

AU - Meeks, Joshua J.

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N2 - The long-term survival of patients with advanced urothelial carcinoma (UCa) is limited because of innate resistance to treatment. We identified elevated expression of the histone methyltransferase EZH2 as a hallmark of aggressive UCa and hypothesized that EZH2 inhibition, via a small-molecule catalytic inhibitor, might have antitumor effects in UCa. Here, in a carcinogen-induced mouse bladder cancer model, a reduction in tumor progression and an increase in immune infiltration upon EZH2 inhibition were observed. Treatment of mice with EZH2i causes an increase in MHC class II expression in the urothelium and can activate infiltrating T cells. Unexpectedly, we found that the lack of an intact adaptive immune system completely abolishes the antitumor effects induced by EZH2 catalytic inhibition. These findings show that immune evasion is the only important determinant for the efficacy of EZH2 catalytic inhibition treatment in a UCa model.

AB - The long-term survival of patients with advanced urothelial carcinoma (UCa) is limited because of innate resistance to treatment. We identified elevated expression of the histone methyltransferase EZH2 as a hallmark of aggressive UCa and hypothesized that EZH2 inhibition, via a small-molecule catalytic inhibitor, might have antitumor effects in UCa. Here, in a carcinogen-induced mouse bladder cancer model, a reduction in tumor progression and an increase in immune infiltration upon EZH2 inhibition were observed. Treatment of mice with EZH2i causes an increase in MHC class II expression in the urothelium and can activate infiltrating T cells. Unexpectedly, we found that the lack of an intact adaptive immune system completely abolishes the antitumor effects induced by EZH2 catalytic inhibition. These findings show that immune evasion is the only important determinant for the efficacy of EZH2 catalytic inhibition treatment in a UCa model.

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Immune activation is essential for the antitumor activity of EZH2 inhibition in urothelial carcinoma

Abstract

Funding

ASJC Scopus subject areas

UN SDGs

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