MYC Induces Immunotherapy and IFNg Resistance Through Downregulation of JAK2

Ettai Markovits; Ortal Harush; Erez N. Baruch; Eldad D. Shulman; Assaf Debby; Orit Itzhaki; Liat Anafi; Artem Danilevsky; Noam Shomron; Guy Ben-Betzalel; Nethanel Asher; Ronnie Shapira-Frommer; Jacob Schachter; Iris Barshack; Tamar Geiger; Ran Elkon; Michal J. Besser; Gal Markel

doi:10.1158/2326-6066.cir-22-0184

MYC Induces Immunotherapy and IFNg Resistance Through Downregulation of JAK2

Ettai Markovits, Ortal Harush, Erez N. Baruch, Eldad D. Shulman, Assaf Debby, Orit Itzhaki, Liat Anafi, Artem Danilevsky, Noam Shomron, Guy Ben-Betzalel, Nethanel Asher, Ronnie Shapira-Frommer, Jacob Schachter, Iris Barshack, Tamar Geiger, Ran Elkon, Michal J. Besser, Gal Markel

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8 Scopus citations

Abstract

Immunotherapy has revolutionized the treatment of advanced melanoma. Because the pathways mediating resistance to immunotherapy are largely unknown, we conducted transcriptome profiling of preimmunotherapy tumor biopsies from patients with melanoma that received PD-1 blockade or adoptive cell therapy with tumor-infiltrating lymphocytes. We identified two melanoma-intrinsic, mutually exclusive gene programs, which were controlled by IFNγ and MYC, and the association with immunotherapy outcome. MYC-overexpressing melanoma cells exhibited lower IFNγ responsiveness, which was linked with JAK2 downregulation. Luciferase activity assays, under the control of JAK2 promoter, demonstrated reduced activity in MYC-overexpressing cells, which was partly reversible upon mutagenesis of a MYC E-box binding site in the JAK2 promoter. Moreover, silencing of MYC or its cofactor MAX with siRNA increased JAK2 expression and IFNγ responsiveness of melanomas, while concomitantly enhancing the effector functions of T cells coincubated with MYC-overexpressing cells. Thus, we propose that MYC plays a pivotal role in immunotherapy resistance through downregulation of JAK2.

Original language	English
Pages (from-to)	909-924
Number of pages	16
Journal	Cancer Immunology Research
Volume	11
Issue number	7
DOIs	https://doi.org/10.1158/2326-6066.cir-22-0184
State	Published - 5 Jul 2023
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2023 American Association for Cancer Research.

Funding

E. Markovits reports personal fees from Nucleai outside the submitted work. T. Geiger reports grants from Israel Science Foundation during the conduct of the study. G. Markel reports personal fees from Roche, MSD, Nucleai, Beyond Air, Biond Biologics, Biomica, Starget, and 4cBiomed; grants and personal fees from Novartis, BMS, Medison, and Sanofi outside the submitted work; and is founder and chief scientificofficer of 4c BioMed; SAB member of Biomica, Biond Biologics, Nucleai; and senior medical advisor of Starget. No disclosures were reported by the other authors. This work was supported by the Melanoma Research Alliance Saban Family Team Science Award and Kamin grant of the Israel Innovation Authority to T. Geiger, N. Shomron, and G. Markel and the Samueli Foundation Grant for Integrative Immuno-Oncology and ISF 3956/19 (IPMP) to G. Markel. Special thanks for the Lemelbaum Family, Aronson Foundation, and Allen Berg Fund for Excellence in Immuno-Oncology for their generous support. The results shown here are in part based upon data generated by TCGA Research Network: https://www.cancer.gov/ tcga. This study was part of E. Markovits and O. Harush’s PhD thesis in the Department of Clinical Immunology and Microbiology at the Sackler Faculty of Medicine, Tel Aviv University.

Funders	Funder number
Aronson Foundation
Lemelbaum family
Samueli Foundation	ISF 3956/19
Melanoma Research Alliance
Israel Science Foundation
Sackler Faculty of Medicine, Tel Aviv University
Israel Innovation Authority

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10.1158/2326-6066.cir-22-0184

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Markovits, E., Harush, O., Baruch, E. N., Shulman, E. D., Debby, A., Itzhaki, O., Anafi, L., Danilevsky, A., Shomron, N., Ben-Betzalel, G., Asher, N., Shapira-Frommer, R., Schachter, J., Barshack, I., Geiger, T., Elkon, R., Besser, M. J., & Markel, G. (2023). MYC Induces Immunotherapy and IFNg Resistance Through Downregulation of JAK2. Cancer Immunology Research, 11(7), 909-924. https://doi.org/10.1158/2326-6066.cir-22-0184

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title = "MYC Induces Immunotherapy and IFNg Resistance Through Downregulation of JAK2",

abstract = "Immunotherapy has revolutionized the treatment of advanced melanoma. Because the pathways mediating resistance to immunotherapy are largely unknown, we conducted transcriptome profiling of preimmunotherapy tumor biopsies from patients with melanoma that received PD-1 blockade or adoptive cell therapy with tumor-infiltrating lymphocytes. We identified two melanoma-intrinsic, mutually exclusive gene programs, which were controlled by IFNγ and MYC, and the association with immunotherapy outcome. MYC-overexpressing melanoma cells exhibited lower IFNγ responsiveness, which was linked with JAK2 downregulation. Luciferase activity assays, under the control of JAK2 promoter, demonstrated reduced activity in MYC-overexpressing cells, which was partly reversible upon mutagenesis of a MYC E-box binding site in the JAK2 promoter. Moreover, silencing of MYC or its cofactor MAX with siRNA increased JAK2 expression and IFNγ responsiveness of melanomas, while concomitantly enhancing the effector functions of T cells coincubated with MYC-overexpressing cells. Thus, we propose that MYC plays a pivotal role in immunotherapy resistance through downregulation of JAK2.",

author = "Ettai Markovits and Ortal Harush and Baruch, {Erez N.} and Shulman, {Eldad D.} and Assaf Debby and Orit Itzhaki and Liat Anafi and Artem Danilevsky and Noam Shomron and Guy Ben-Betzalel and Nethanel Asher and Ronnie Shapira-Frommer and Jacob Schachter and Iris Barshack and Tamar Geiger and Ran Elkon and Besser, {Michal J.} and Gal Markel",

note = "Publisher Copyright: {\textcopyright} 2023 American Association for Cancer Research.",

year = "2023",

month = jul,

day = "5",

doi = "10.1158/2326-6066.cir-22-0184",

language = "אנגלית",

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Markovits, E, Harush, O, Baruch, EN, Shulman, ED, Debby, A, Itzhaki, O, Anafi, L, Danilevsky, A, Shomron, N, Ben-Betzalel, G, Asher, N, Shapira-Frommer, R, Schachter, J, Barshack, I, Geiger, T, Elkon, R, Besser, MJ & Markel, G 2023, 'MYC Induces Immunotherapy and IFNg Resistance Through Downregulation of JAK2', Cancer Immunology Research, vol. 11, no. 7, pp. 909-924. https://doi.org/10.1158/2326-6066.cir-22-0184

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AU - Markovits, Ettai

AU - Harush, Ortal

AU - Baruch, Erez N.

AU - Shulman, Eldad D.

AU - Debby, Assaf

AU - Itzhaki, Orit

AU - Anafi, Liat

AU - Danilevsky, Artem

AU - Shomron, Noam

AU - Ben-Betzalel, Guy

AU - Asher, Nethanel

AU - Shapira-Frommer, Ronnie

AU - Schachter, Jacob

AU - Barshack, Iris

AU - Geiger, Tamar

AU - Elkon, Ran

AU - Besser, Michal J.

AU - Markel, Gal

PY - 2023/7/5

Y1 - 2023/7/5

N2 - Immunotherapy has revolutionized the treatment of advanced melanoma. Because the pathways mediating resistance to immunotherapy are largely unknown, we conducted transcriptome profiling of preimmunotherapy tumor biopsies from patients with melanoma that received PD-1 blockade or adoptive cell therapy with tumor-infiltrating lymphocytes. We identified two melanoma-intrinsic, mutually exclusive gene programs, which were controlled by IFNγ and MYC, and the association with immunotherapy outcome. MYC-overexpressing melanoma cells exhibited lower IFNγ responsiveness, which was linked with JAK2 downregulation. Luciferase activity assays, under the control of JAK2 promoter, demonstrated reduced activity in MYC-overexpressing cells, which was partly reversible upon mutagenesis of a MYC E-box binding site in the JAK2 promoter. Moreover, silencing of MYC or its cofactor MAX with siRNA increased JAK2 expression and IFNγ responsiveness of melanomas, while concomitantly enhancing the effector functions of T cells coincubated with MYC-overexpressing cells. Thus, we propose that MYC plays a pivotal role in immunotherapy resistance through downregulation of JAK2.

AB - Immunotherapy has revolutionized the treatment of advanced melanoma. Because the pathways mediating resistance to immunotherapy are largely unknown, we conducted transcriptome profiling of preimmunotherapy tumor biopsies from patients with melanoma that received PD-1 blockade or adoptive cell therapy with tumor-infiltrating lymphocytes. We identified two melanoma-intrinsic, mutually exclusive gene programs, which were controlled by IFNγ and MYC, and the association with immunotherapy outcome. MYC-overexpressing melanoma cells exhibited lower IFNγ responsiveness, which was linked with JAK2 downregulation. Luciferase activity assays, under the control of JAK2 promoter, demonstrated reduced activity in MYC-overexpressing cells, which was partly reversible upon mutagenesis of a MYC E-box binding site in the JAK2 promoter. Moreover, silencing of MYC or its cofactor MAX with siRNA increased JAK2 expression and IFNγ responsiveness of melanomas, while concomitantly enhancing the effector functions of T cells coincubated with MYC-overexpressing cells. Thus, we propose that MYC plays a pivotal role in immunotherapy resistance through downregulation of JAK2.

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MYC Induces Immunotherapy and IFNg Resistance Through Downregulation of JAK2

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