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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 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 languageEnglish
Pages (from-to)909-924
Number of pages16
JournalCancer immunology research
Volume11
Issue number7
DOIs
StatePublished - 1 Jul 2023

Funding

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

    Fingerprint

    Dive into the research topics of 'MYC Induces Immunotherapy and IFNg Resistance Through Downregulation of JAK2'. Together they form a unique fingerprint.

    Cite this