TY - JOUR
T1 - MYC Induces Immunotherapy and IFNg Resistance Through Downregulation of JAK2
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
N1 - Publisher Copyright:
© 2023 American Association for Cancer Research.
PY - 2023/7/1
Y1 - 2023/7/1
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.
UR - http://www.scopus.com/inward/record.url?scp=85164243771&partnerID=8YFLogxK
U2 - 10.1158/2326-6066.CIR-22-0184
DO - 10.1158/2326-6066.CIR-22-0184
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C2 - 37074069
AN - SCOPUS:85164243771
SN - 2326-6066
VL - 11
SP - 909
EP - 924
JO - Cancer immunology research
JF - Cancer immunology research
IS - 7
ER -
