Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML

Jessica M. Salmon; Izabela Todorovski; Kym L. Stanley; Claudia Bruedigam; Conor J. Kearney; Luciano G. Martelotto; Fernando Rossello; Timothy Semple; Gisela Mir Arnau; Magnus Zethoven; Michael Bots; Stefan Bjelosevic; Leonie A. Cluse; Peter J. Fraser; Veronique Litalien; Eva Vidacs; Kate McArthur; Antony Y. Matthews; Elise Gressier; Nicole A. De Weerd; Jens Lichte; Madison J. Kelly; Simon J. Hogg; Paul J. Hertzog; Lev M. Kats; Stephin J. Vervoort; Daniel D. De Carvalho; Stefanie Scheu; Sammy Bedoui; Benjamin T. Kile; Steven W. Lane; Andrew C. Perkins; Andrew H. Wei; Pilar M. Dominguez; Ricky W. Johnstone

doi:10.1158/2159-8290.CD-20-1145

Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML

Jessica M. Salmon, Izabela Todorovski, Kym L. Stanley, Claudia Bruedigam, Conor J. Kearney, Luciano G. Martelotto, Fernando Rossello, Timothy Semple, Gisela Mir Arnau, Magnus Zethoven, Michael Bots, Stefan Bjelosevic, Leonie A. Cluse, Peter J. Fraser, Veronique Litalien, Eva Vidacs, Kate McArthur, Antony Y. Matthews, Elise Gressier, Nicole A. De WeerdJens Lichte, Madison J. Kelly, Simon J. Hogg, Paul J. Hertzog, Lev M. Kats, Stephin J. Vervoort, Daniel D. De Carvalho, Stefanie Scheu, Sammy Bedoui, Benjamin T. Kile, Steven W. Lane, Andrew C. Perkins, Andrew H. Wei, Pilar M. Dominguez, Ricky W. Johnstone

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

2 Citations (Scopus)

Abstract

Pharmacologic inhibition of epigenetic enzymes can have therapeutic benefit against hematologic malignancies. In addition to affecting tumor cell growth and proliferation, these epigenetic agents may induce antitumor immunity. Here, we discovered a novel immunoregulatory mechanism through inhibition of histone deacetylases (HDAC). In models of acute myeloid leukemia (AML), leukemia cell differentiation and therapeutic benefit mediated by the HDAC inhibitor (HDACi) panobinostat required activation of the type I interferon (IFN) pathway. Plasmacytoid dendritic cells (pDC) produced type I IFN after panobinostat treatment, through transcriptional activation of IFN genes concomitant with increased H3K27 acetylation at these loci. Depletion of pDCs abrogated panobinostat-mediated induction of type I IFN signaling in leukemia cells and impaired therapeutic efficacy, whereas combined treatment with panobinostat and IFNα improved outcomes in preclinical models. These discoveries offer a new therapeutic approach for AML and demonstrate that epigenetic rewiring of pDCs enhances antitumor immunity, opening the possibility of exploiting this approach for immunotherapies.

Original language	English
Pages (from-to)	1560-1579
Number of pages	20
Journal	Cancer Discovery
Volume	12
Issue number	6
DOIs	https://doi.org/10.1158/2159-8290.CD-20-1145
Publication status	Published - Jun 2022

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10.1158/2159-8290.CD-20-1145Licence: CC BY-NC-ND

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Salmon, J. M., Todorovski, I., Stanley, K. L., Bruedigam, C., Kearney, C. J., Martelotto, L. G., Rossello, F., Semple, T., Arnau, G. M., Zethoven, M., Bots, M., Bjelosevic, S., Cluse, L. A., Fraser, P. J., Litalien, V., Vidacs, E., McArthur, K., Matthews, A. Y., Gressier, E., ... Johnstone, R. W. (2022). Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML. Cancer Discovery, 12(6), 1560-1579. https://doi.org/10.1158/2159-8290.CD-20-1145

@article{fd5ba32dd4de44538765f81037e5715f,

title = "Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML",

abstract = "Pharmacologic inhibition of epigenetic enzymes can have therapeutic benefit against hematologic malignancies. In addition to affecting tumor cell growth and proliferation, these epigenetic agents may induce antitumor immunity. Here, we discovered a novel immunoregulatory mechanism through inhibition of histone deacetylases (HDAC). In models of acute myeloid leukemia (AML), leukemia cell differentiation and therapeutic benefit mediated by the HDAC inhibitor (HDACi) panobinostat required activation of the type I interferon (IFN) pathway. Plasmacytoid dendritic cells (pDC) produced type I IFN after panobinostat treatment, through transcriptional activation of IFN genes concomitant with increased H3K27 acetylation at these loci. Depletion of pDCs abrogated panobinostat-mediated induction of type I IFN signaling in leukemia cells and impaired therapeutic efficacy, whereas combined treatment with panobinostat and IFNα improved outcomes in preclinical models. These discoveries offer a new therapeutic approach for AML and demonstrate that epigenetic rewiring of pDCs enhances antitumor immunity, opening the possibility of exploiting this approach for immunotherapies.",

author = "Salmon, {Jessica M.} and Izabela Todorovski and Stanley, {Kym L.} and Claudia Bruedigam and Kearney, {Conor J.} and Martelotto, {Luciano G.} and Fernando Rossello and Timothy Semple and Arnau, {Gisela Mir} and Magnus Zethoven and Michael Bots and Stefan Bjelosevic and Cluse, {Leonie A.} and Fraser, {Peter J.} and Veronique Litalien and Eva Vidacs and Kate McArthur and Matthews, {Antony Y.} and Elise Gressier and {De Weerd}, {Nicole A.} and Jens Lichte and Kelly, {Madison J.} and Hogg, {Simon J.} and Hertzog, {Paul J.} and Kats, {Lev M.} and Vervoort, {Stephin J.} and {De Carvalho}, {Daniel D.} and Stefanie Scheu and Sammy Bedoui and Kile, {Benjamin T.} and Lane, {Steven W.} and Perkins, {Andrew C.} and Wei, {Andrew H.} and Dominguez, {Pilar M.} and Johnstone, {Ricky W.}",

note = "Funding Information: F. Rossello reports grants from the National Health and Medical Research Council (Australia), and other support from The Lorenzo and Pamela Galli Medical Research Trust and The PMF Foundation during the conduct of the study. S. Bjelosevic reports grants from Cancer Council Victoria during the conduct of the study. J. Lichte reports grants from the German Research Foundation (DFG) during the conduct of the study. S.J. Hogg reports grants from Cancer Council Victoria and the National Health and Medical Research Council of Australia during the conduct of the study. L.M. Kats reports grants and personal fees from Agios Pharmaceuticals, and grants from Servier Pharmaceuticals and Biocurate outside the submitted work. D.D. De Carvalho reports other support from Adela and grants from Pfizer outside the submitted work. S. Scheu reports grants from the German Research Foundation (DFG) during the conduct of the study, as well as a patent for bicistronic mRNA licensed and with royalties paid. S.W. Lane reports personal fees from Novartis, AbbVie, and Astellas, and grants from Celgene/Bristol Myers Squibb outside the submitted work. A.H. Wei reports nonfinancial support from Helsinn and grants, personal fees, and nonfinancial support from Novartis during the conduct of the study; grants, personal fees, and nonfinancial support from AbbVie and Bristol Myers Squibb, and grants and personal fees from Servier, Pfizer, AstraZeneca, Janssen, and Amgen outside the submitted work; and is an employee of the Walter and Eliza Hall Institute of Medical Research and eligible for royalty payments in relation to venetoclax. R.W. Johnstone reports grants, personal fees, and nonfinancial support from Novartis during the conduct of the study, as well as grants from Roche, Bristol Myers Squibb, and AstraZeneca, and grants and personal fees from MycRx outside the submitted work. No disclosures were reported by the other authors. Funding Information: We thank staff from the Animal Facility, Genotyping Core, Flow Cytometry Facility, Molecular Genomics Core, Victorian Center for Functional Genomics, Centre for Advanced Histology and Microscopy and Bioinformatics Consulting Core of the Peter MacCallum Cancer Centre, and members of the Johnstone laboratory for useful discussions. We acknowledge Nicole Messina and Dan Andrews for providing reagents and advice and support from the Peter MacCallum Cancer Centre Foundation and Australian Cancer Research Foundation. We also thank the Monash Histology Platform and Gareth Gregory for processing and assessing, respectively, the histology sections from the PDX models. Research reported in this publication was supported by Cure Cancer Australia under award number 1051444, awarded to J.M. Salmon and R.W. Johnstone. I. Todorovski was supported by an Australian Research Training Program (RTP) Scholarship during this study; S.J. Vervoort was supported by a Rubicon Fellowship from the Netherlands Organization for Scientific Research (NWO; 019.161LW.017), a National Health and Medical Research Council (NHMRC) EL1 Fellowship (GNT1178339), and a Peter MacCallum Cancer Foundation Grant; S.J. Hogg was supported by a Postdoctoral Fellowship from Cancer Council Victoria (CCV); L.G. Martelotto and Single Cell Innovation Lab were supported by The Lorenzo and Pamela Galli Research Fund Trust; L.M. Kats was supported by a Victorian Cancer Agency Fellowship (MCRF15003); S. Scheu was supported by the German Research Foundation (DFG; 270650915/GRK2158 and SCHE692/6-1) and the Manchot Graduate School “Molecules of Infection III”; D.D. De Carvalho is funded by the Canadian Institute of Health Research (201512MSH360794-228629, FDN 148430, and PJT 165986) and the Canada Research Chairs; B.T. Kile is funded by a Project Grant from NHMRC (Grant No. 1113577) and an NHMRC Principal Research Fellowship (No. 1063008); P.M. Dominguez was supported by a Postdoctoral Fellowship Grant from the Lymphoma Research Foundation and is funded by an Ideas Grant from the NHMRC (GNT2011217); and R.W. Johnstone is funded by a Project Grant from CCV, a Project Grant and Program Grant (grant 454569) from the NHMRC, an NHMRC Senior Principal Research Fellowship, and a Grant from The Kids{\textquoteright} Cancer Project (to R.W. Johnstone and S.J. Vervoort). Publisher Copyright: {\textcopyright} 2022 The Authors; Published by the American Association for Cancer Research.",

year = "2022",

month = jun,

doi = "10.1158/2159-8290.CD-20-1145",

language = "English",

volume = "12",

pages = "1560--1579",

journal = "Cancer Discovery",

issn = "2159-8274",

publisher = "American Association for Cancer Research (AACR)",

number = "6",

}

Salmon, JM, Todorovski, I, Stanley, KL, Bruedigam, C, Kearney, CJ, Martelotto, LG, Rossello, F, Semple, T, Arnau, GM, Zethoven, M, Bots, M, Bjelosevic, S, Cluse, LA, Fraser, PJ, Litalien, V, Vidacs, E, McArthur, K, Matthews, AY, Gressier, E, De Weerd, NA, Lichte, J, Kelly, MJ, Hogg, SJ, Hertzog, PJ, Kats, LM, Vervoort, SJ, De Carvalho, DD, Scheu, S, Bedoui, S, Kile, BT, Lane, SW, Perkins, AC , Wei, AH, Dominguez, PM & Johnstone, RW 2022, 'Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML', Cancer Discovery, vol. 12, no. 6, pp. 1560-1579. https://doi.org/10.1158/2159-8290.CD-20-1145

TY - JOUR

T1 - Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML

AU - Salmon, Jessica M.

AU - Todorovski, Izabela

AU - Stanley, Kym L.

AU - Bruedigam, Claudia

AU - Kearney, Conor J.

AU - Martelotto, Luciano G.

AU - Rossello, Fernando

AU - Semple, Timothy

AU - Arnau, Gisela Mir

AU - Zethoven, Magnus

AU - Bots, Michael

AU - Bjelosevic, Stefan

AU - Cluse, Leonie A.

AU - Fraser, Peter J.

AU - Litalien, Veronique

AU - Vidacs, Eva

AU - McArthur, Kate

AU - Matthews, Antony Y.

AU - Gressier, Elise

AU - De Weerd, Nicole A.

AU - Lichte, Jens

AU - Kelly, Madison J.

AU - Hogg, Simon J.

AU - Hertzog, Paul J.

AU - Kats, Lev M.

AU - Vervoort, Stephin J.

AU - De Carvalho, Daniel D.

AU - Scheu, Stefanie

AU - Bedoui, Sammy

AU - Kile, Benjamin T.

AU - Lane, Steven W.

AU - Perkins, Andrew C.

AU - Wei, Andrew H.

AU - Dominguez, Pilar M.

AU - Johnstone, Ricky W.

N1 - Funding Information: F. Rossello reports grants from the National Health and Medical Research Council (Australia), and other support from The Lorenzo and Pamela Galli Medical Research Trust and The PMF Foundation during the conduct of the study. S. Bjelosevic reports grants from Cancer Council Victoria during the conduct of the study. J. Lichte reports grants from the German Research Foundation (DFG) during the conduct of the study. S.J. Hogg reports grants from Cancer Council Victoria and the National Health and Medical Research Council of Australia during the conduct of the study. L.M. Kats reports grants and personal fees from Agios Pharmaceuticals, and grants from Servier Pharmaceuticals and Biocurate outside the submitted work. D.D. De Carvalho reports other support from Adela and grants from Pfizer outside the submitted work. S. Scheu reports grants from the German Research Foundation (DFG) during the conduct of the study, as well as a patent for bicistronic mRNA licensed and with royalties paid. S.W. Lane reports personal fees from Novartis, AbbVie, and Astellas, and grants from Celgene/Bristol Myers Squibb outside the submitted work. A.H. Wei reports nonfinancial support from Helsinn and grants, personal fees, and nonfinancial support from Novartis during the conduct of the study; grants, personal fees, and nonfinancial support from AbbVie and Bristol Myers Squibb, and grants and personal fees from Servier, Pfizer, AstraZeneca, Janssen, and Amgen outside the submitted work; and is an employee of the Walter and Eliza Hall Institute of Medical Research and eligible for royalty payments in relation to venetoclax. R.W. Johnstone reports grants, personal fees, and nonfinancial support from Novartis during the conduct of the study, as well as grants from Roche, Bristol Myers Squibb, and AstraZeneca, and grants and personal fees from MycRx outside the submitted work. No disclosures were reported by the other authors. Funding Information: We thank staff from the Animal Facility, Genotyping Core, Flow Cytometry Facility, Molecular Genomics Core, Victorian Center for Functional Genomics, Centre for Advanced Histology and Microscopy and Bioinformatics Consulting Core of the Peter MacCallum Cancer Centre, and members of the Johnstone laboratory for useful discussions. We acknowledge Nicole Messina and Dan Andrews for providing reagents and advice and support from the Peter MacCallum Cancer Centre Foundation and Australian Cancer Research Foundation. We also thank the Monash Histology Platform and Gareth Gregory for processing and assessing, respectively, the histology sections from the PDX models. Research reported in this publication was supported by Cure Cancer Australia under award number 1051444, awarded to J.M. Salmon and R.W. Johnstone. I. Todorovski was supported by an Australian Research Training Program (RTP) Scholarship during this study; S.J. Vervoort was supported by a Rubicon Fellowship from the Netherlands Organization for Scientific Research (NWO; 019.161LW.017), a National Health and Medical Research Council (NHMRC) EL1 Fellowship (GNT1178339), and a Peter MacCallum Cancer Foundation Grant; S.J. Hogg was supported by a Postdoctoral Fellowship from Cancer Council Victoria (CCV); L.G. Martelotto and Single Cell Innovation Lab were supported by The Lorenzo and Pamela Galli Research Fund Trust; L.M. Kats was supported by a Victorian Cancer Agency Fellowship (MCRF15003); S. Scheu was supported by the German Research Foundation (DFG; 270650915/GRK2158 and SCHE692/6-1) and the Manchot Graduate School “Molecules of Infection III”; D.D. De Carvalho is funded by the Canadian Institute of Health Research (201512MSH360794-228629, FDN 148430, and PJT 165986) and the Canada Research Chairs; B.T. Kile is funded by a Project Grant from NHMRC (Grant No. 1113577) and an NHMRC Principal Research Fellowship (No. 1063008); P.M. Dominguez was supported by a Postdoctoral Fellowship Grant from the Lymphoma Research Foundation and is funded by an Ideas Grant from the NHMRC (GNT2011217); and R.W. Johnstone is funded by a Project Grant from CCV, a Project Grant and Program Grant (grant 454569) from the NHMRC, an NHMRC Senior Principal Research Fellowship, and a Grant from The Kids’ Cancer Project (to R.W. Johnstone and S.J. Vervoort). Publisher Copyright: © 2022 The Authors; Published by the American Association for Cancer Research.

PY - 2022/6

Y1 - 2022/6

N2 - Pharmacologic inhibition of epigenetic enzymes can have therapeutic benefit against hematologic malignancies. In addition to affecting tumor cell growth and proliferation, these epigenetic agents may induce antitumor immunity. Here, we discovered a novel immunoregulatory mechanism through inhibition of histone deacetylases (HDAC). In models of acute myeloid leukemia (AML), leukemia cell differentiation and therapeutic benefit mediated by the HDAC inhibitor (HDACi) panobinostat required activation of the type I interferon (IFN) pathway. Plasmacytoid dendritic cells (pDC) produced type I IFN after panobinostat treatment, through transcriptional activation of IFN genes concomitant with increased H3K27 acetylation at these loci. Depletion of pDCs abrogated panobinostat-mediated induction of type I IFN signaling in leukemia cells and impaired therapeutic efficacy, whereas combined treatment with panobinostat and IFNα improved outcomes in preclinical models. These discoveries offer a new therapeutic approach for AML and demonstrate that epigenetic rewiring of pDCs enhances antitumor immunity, opening the possibility of exploiting this approach for immunotherapies.

AB - Pharmacologic inhibition of epigenetic enzymes can have therapeutic benefit against hematologic malignancies. In addition to affecting tumor cell growth and proliferation, these epigenetic agents may induce antitumor immunity. Here, we discovered a novel immunoregulatory mechanism through inhibition of histone deacetylases (HDAC). In models of acute myeloid leukemia (AML), leukemia cell differentiation and therapeutic benefit mediated by the HDAC inhibitor (HDACi) panobinostat required activation of the type I interferon (IFN) pathway. Plasmacytoid dendritic cells (pDC) produced type I IFN after panobinostat treatment, through transcriptional activation of IFN genes concomitant with increased H3K27 acetylation at these loci. Depletion of pDCs abrogated panobinostat-mediated induction of type I IFN signaling in leukemia cells and impaired therapeutic efficacy, whereas combined treatment with panobinostat and IFNα improved outcomes in preclinical models. These discoveries offer a new therapeutic approach for AML and demonstrate that epigenetic rewiring of pDCs enhances antitumor immunity, opening the possibility of exploiting this approach for immunotherapies.

UR - http://www.scopus.com/inward/record.url?scp=85134034852&partnerID=8YFLogxK

U2 - 10.1158/2159-8290.CD-20-1145

DO - 10.1158/2159-8290.CD-20-1145

M3 - Article

C2 - 35311997

AN - SCOPUS:85134034852

VL - 12

SP - 1560

EP - 1579

JO - Cancer Discovery

JF - Cancer Discovery

SN - 2159-8274

IS - 6

ER -

Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML

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