EZH2 inhibition activates a dsRNA–STING–interferon stress axis that potentiates response to PD-1 checkpoint blockade in prostate cancer

Katherine L. Morel; Anjali V. Sheahan; Deborah L. Burkhart; Sylvan C. Baca; Nadia Boufaied; Yin Liu; Xintao Qiu; Israel Cañadas; Kevin Roehle; Max Heckler; Carla Calagua; Huihui Ye; Constantia Pantelidou; Phillip Galbo; Sukanya Panja; Antonina Mitrofanova; Scott Wilkinson; Nichelle C. Whitlock; Shana Y. Trostel; Anis A. Hamid; Adam S. Kibel; David A. Barbie; Atish D. Choudhury; Mark M. Pomerantz; Christopher J. Sweeney; Henry W. Long; David J. Einstein; Geoffrey I. Shapiro; Stephanie K. Dougan; Adam G. Sowalsky; Housheng Hansen He; Matthew L. Freedman; Steven P. Balk; Massimo Loda; David P. Labbé; Brian M. Olson; Leigh Ellis

doi:10.1038/s43018-021-00185-w

EZH2 inhibition activates a dsRNA–STING–interferon stress axis that potentiates response to PD-1 checkpoint blockade in prostate cancer

Katherine L. Morel, Anjali V. Sheahan, Deborah L. Burkhart, Sylvan C. Baca, Nadia Boufaied, Yin Liu, Xintao Qiu, Israel Cañadas, Kevin Roehle, Max Heckler, Carla Calagua, Huihui Ye, Constantia Pantelidou, Phillip Galbo, Sukanya Panja, Antonina Mitrofanova, Scott Wilkinson, Nichelle C. Whitlock, Shana Y. Trostel, Anis A. HamidAdam S. Kibel, David A. Barbie, Atish D. Choudhury, Mark M. Pomerantz, Christopher J. Sweeney, Henry W. Long, David J. Einstein, Geoffrey I. Shapiro, Stephanie K. Dougan, Adam G. Sowalsky, Housheng Hansen He, Matthew L. Freedman, Steven P. Balk, Massimo Loda, David P. Labbé, Brian M. Olson, Leigh Ellis^*

^*Corresponding author for this work

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Abstract

Prostate cancers are considered to be immunologically ‘cold’ tumors given the very few patients who respond to checkpoint inhibitor (CPI) therapy. Recently, enrichment of interferon-stimulated genes (ISGs) predicted a favorable response to CPI across various disease sites. The enhancer of zeste homolog-2 (EZH2) is overexpressed in prostate cancer and known to negatively regulate ISGs. In the present study, we demonstrate that EZH2 inhibition in prostate cancer models activates a double-stranded RNA–STING–ISG stress response upregulating genes involved in antigen presentation, Th1 chemokine signaling and interferon response, including programmed cell death protein 1 (PD-L1) that is dependent on STING activation. EZH2 inhibition substantially increased intratumoral trafficking of activated CD8⁺ T cells and increased M1 tumor-associated macrophages, overall reversing resistance to PD-1 CPI. Our study identifies EZH2 as a potent inhibitor of antitumor immunity and responsiveness to CPI. These data suggest EZH2 inhibition as a therapeutic direction to enhance prostate cancer response to PD-1 CPI.

Original language	English
Pages (from-to)	444-456
Number of pages	13
Journal	Nature Cancer
Volume	2
Issue number	4
DOIs	https://doi.org/10.1038/s43018-021-00185-w
State	Published - Apr 2021

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Morel, K. L., Sheahan, A. V., Burkhart, D. L., Baca, S. C., Boufaied, N., Liu, Y., Qiu, X., Cañadas, I., Roehle, K., Heckler, M., Calagua, C., Ye, H., Pantelidou, C., Galbo, P., Panja, S., Mitrofanova, A., Wilkinson, S., Whitlock, N. C., Trostel, S. Y., ... Ellis, L. (2021). EZH2 inhibition activates a dsRNA–STING–interferon stress axis that potentiates response to PD-1 checkpoint blockade in prostate cancer. Nature Cancer, 2(4), 444-456. https://doi.org/10.1038/s43018-021-00185-w

@article{b312c5fbae6b4dd693a54dd8a34b5744,

title = "EZH2 inhibition activates a dsRNA–STING–interferon stress axis that potentiates response to PD-1 checkpoint blockade in prostate cancer",

abstract = "Prostate cancers are considered to be immunologically {\textquoteleft}cold{\textquoteright} tumors given the very few patients who respond to checkpoint inhibitor (CPI) therapy. Recently, enrichment of interferon-stimulated genes (ISGs) predicted a favorable response to CPI across various disease sites. The enhancer of zeste homolog-2 (EZH2) is overexpressed in prostate cancer and known to negatively regulate ISGs. In the present study, we demonstrate that EZH2 inhibition in prostate cancer models activates a double-stranded RNA–STING–ISG stress response upregulating genes involved in antigen presentation, Th1 chemokine signaling and interferon response, including programmed cell death protein 1 (PD-L1) that is dependent on STING activation. EZH2 inhibition substantially increased intratumoral trafficking of activated CD8+ T cells and increased M1 tumor-associated macrophages, overall reversing resistance to PD-1 CPI. Our study identifies EZH2 as a potent inhibitor of antitumor immunity and responsiveness to CPI. These data suggest EZH2 inhibition as a therapeutic direction to enhance prostate cancer response to PD-1 CPI.",

author = "Morel, {Katherine L.} and Sheahan, {Anjali V.} and Burkhart, {Deborah L.} and Baca, {Sylvan C.} and Nadia Boufaied and Yin Liu and Xintao Qiu and Israel Ca{\~n}adas and Kevin Roehle and Max Heckler and Carla Calagua and Huihui Ye and Constantia Pantelidou and Phillip Galbo and Sukanya Panja and Antonina Mitrofanova and Scott Wilkinson and Whitlock, {Nichelle C.} and Trostel, {Shana Y.} and Hamid, {Anis A.} and Kibel, {Adam S.} and Barbie, {David A.} and Choudhury, {Atish D.} and Pomerantz, {Mark M.} and Sweeney, {Christopher J.} and Long, {Henry W.} and Einstein, {David J.} and Shapiro, {Geoffrey I.} and Dougan, {Stephanie K.} and Sowalsky, {Adam G.} and He, {Housheng Hansen} and Freedman, {Matthew L.} and Balk, {Steven P.} and Massimo Loda and Labb{\'e}, {David P.} and Olson, {Brian M.} and Leigh Ellis",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature America, Inc. part of Springer Nature.",

year = "2021",

month = apr,

doi = "10.1038/s43018-021-00185-w",

language = "English",

volume = "2",

pages = "444--456",

journal = "Nature Cancer",

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Morel, KL, Sheahan, AV, Burkhart, DL, Baca, SC, Boufaied, N, Liu, Y, Qiu, X, Cañadas, I, Roehle, K, Heckler, M, Calagua, C, Ye, H, Pantelidou, C, Galbo, P, Panja, S, Mitrofanova, A, Wilkinson, S, Whitlock, NC, Trostel, SY, Hamid, AA, Kibel, AS, Barbie, DA, Choudhury, AD, Pomerantz, MM, Sweeney, CJ, Long, HW, Einstein, DJ, Shapiro, GI, Dougan, SK, Sowalsky, AG, He, HH, Freedman, ML, Balk, SP, Loda, M, Labbé, DP, Olson, BM & Ellis, L 2021, 'EZH2 inhibition activates a dsRNA–STING–interferon stress axis that potentiates response to PD-1 checkpoint blockade in prostate cancer', Nature Cancer, vol. 2, no. 4, pp. 444-456. https://doi.org/10.1038/s43018-021-00185-w

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AU - Morel, Katherine L.

AU - Sheahan, Anjali V.

AU - Burkhart, Deborah L.

AU - Baca, Sylvan C.

AU - Boufaied, Nadia

AU - Liu, Yin

AU - Qiu, Xintao

AU - Cañadas, Israel

AU - Roehle, Kevin

AU - Heckler, Max

AU - Calagua, Carla

AU - Ye, Huihui

AU - Pantelidou, Constantia

AU - Galbo, Phillip

AU - Panja, Sukanya

AU - Mitrofanova, Antonina

AU - Wilkinson, Scott

AU - Whitlock, Nichelle C.

AU - Trostel, Shana Y.

AU - Hamid, Anis A.

AU - Kibel, Adam S.

AU - Barbie, David A.

AU - Choudhury, Atish D.

AU - Pomerantz, Mark M.

AU - Sweeney, Christopher J.

AU - Long, Henry W.

AU - Einstein, David J.

AU - Shapiro, Geoffrey I.

AU - Dougan, Stephanie K.

AU - Sowalsky, Adam G.

AU - He, Housheng Hansen

AU - Freedman, Matthew L.

AU - Balk, Steven P.

AU - Loda, Massimo

AU - Labbé, David P.

AU - Olson, Brian M.

AU - Ellis, Leigh

PY - 2021/4

Y1 - 2021/4

N2 - Prostate cancers are considered to be immunologically ‘cold’ tumors given the very few patients who respond to checkpoint inhibitor (CPI) therapy. Recently, enrichment of interferon-stimulated genes (ISGs) predicted a favorable response to CPI across various disease sites. The enhancer of zeste homolog-2 (EZH2) is overexpressed in prostate cancer and known to negatively regulate ISGs. In the present study, we demonstrate that EZH2 inhibition in prostate cancer models activates a double-stranded RNA–STING–ISG stress response upregulating genes involved in antigen presentation, Th1 chemokine signaling and interferon response, including programmed cell death protein 1 (PD-L1) that is dependent on STING activation. EZH2 inhibition substantially increased intratumoral trafficking of activated CD8+ T cells and increased M1 tumor-associated macrophages, overall reversing resistance to PD-1 CPI. Our study identifies EZH2 as a potent inhibitor of antitumor immunity and responsiveness to CPI. These data suggest EZH2 inhibition as a therapeutic direction to enhance prostate cancer response to PD-1 CPI.

AB - Prostate cancers are considered to be immunologically ‘cold’ tumors given the very few patients who respond to checkpoint inhibitor (CPI) therapy. Recently, enrichment of interferon-stimulated genes (ISGs) predicted a favorable response to CPI across various disease sites. The enhancer of zeste homolog-2 (EZH2) is overexpressed in prostate cancer and known to negatively regulate ISGs. In the present study, we demonstrate that EZH2 inhibition in prostate cancer models activates a double-stranded RNA–STING–ISG stress response upregulating genes involved in antigen presentation, Th1 chemokine signaling and interferon response, including programmed cell death protein 1 (PD-L1) that is dependent on STING activation. EZH2 inhibition substantially increased intratumoral trafficking of activated CD8+ T cells and increased M1 tumor-associated macrophages, overall reversing resistance to PD-1 CPI. Our study identifies EZH2 as a potent inhibitor of antitumor immunity and responsiveness to CPI. These data suggest EZH2 inhibition as a therapeutic direction to enhance prostate cancer response to PD-1 CPI.

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U2 - 10.1038/s43018-021-00185-w

DO - 10.1038/s43018-021-00185-w

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JO - Nature Cancer

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