TY  - JOUR
AU  - Langenbach, Marlene
AU  - Giesler, Sophie
AU  - Richtsfeld, Stefan
AU  - Costa-Pereira, Sara
AU  - Rindlisbacher, Lukas
AU  - Wertheimer, Tobias
AU  - Braun, Lukas M
AU  - Andrieux, Geoffroy
AU  - Duquesne, Sandra
AU  - Pfeifer, Dietmar
AU  - Woessner, Nadine M
AU  - Menssen, Hans D
AU  - Taromi, Sanaz
AU  - Duyster, Justus
AU  - Börries, Melanie
AU  - Brummer, Tilman
AU  - Blazar, Bruce R
AU  - Minguet, Susana
AU  - Turko, Patrick
AU  - Levesque, Mitchell P
AU  - Becher, Burkhard
AU  - Zeiser, Robert
TI  - MDM2 Inhibition Enhances Immune Checkpoint Inhibitor Efficacy by Increasing IL15 and MHC Class II Production.
JO  - Molecular cancer research
VL  - 21
IS  - 8
SN  - 1541-7786
CY  - Philadelphia, Pa.
PB  - AACR
M1  - DKFZ-2023-01568
SP  - 849 - 864
PY  - 2023
AB  - The treatment of patients with metastatic melanoma with immune checkpoint inhibitors (ICI) leads to impressive response rates but primary and secondary resistance to ICI reduces progression-free survival. Novel strategies that interfere with resistance mechanisms are key to further improve patient outcome during ICI therapy. P53 is often inactivated by mouse-double-minute-2 (MDM2), which may decrease immunogenicity of melanoma cells. We analyzed primary patient-derived melanoma cell lines, performed bulk sequencing analysis of patient-derived melanoma samples, and used melanoma mouse models to investigate the role of MDM2-inhibition for enhanced ICI therapy. We found increased expression of IL15 and MHC-II in murine melanoma cells upon p53 induction by MDM2-inhibition. MDM2-inhibitor induced MHC-II and IL15-production, which was p53 dependent as Tp53 knockdown blocked the effect. Lack of IL15-receptor in hematopoietic cells or IL15 neutralization reduced the MDM2-inhibition/p53-induction-mediated antitumor immunity. P53 induction by MDM2-inhibition caused anti-melanoma immune memory as T cells isolated from MDM2-inhibitor-treated melanoma-bearing mice exhibited anti-melanoma activity in secondary melanoma-bearing mice. In patient-derived melanoma cells p53 induction by MDM2-inhibition increased IL15 and MHC-II. IL15 and CIITA expressions were associated with a more favorable prognosis in patients bearing WT but not TP53-mutated melanoma.MDM2-inhibition represents a novel strategy to enhance IL15 and MHC-II-production, which disrupts the immunosuppressive tumor microenvironment. On the basis of our findings, a clinical trial combining MDM2-inhibition with anti-PD-1 immunotherapy for metastatic melanoma is planned.
KW  - Animals
KW  - Mice
KW  - Tumor Suppressor Protein p53: genetics
KW  - Tumor Suppressor Protein p53: metabolism
KW  - Interleukin-15: metabolism
KW  - Interleukin-15: therapeutic use
KW  - Immune Checkpoint Inhibitors: pharmacology
KW  - Immune Checkpoint Inhibitors: therapeutic use
KW  - Cell Line, Tumor
KW  - Melanoma: drug therapy
KW  - Melanoma: genetics
KW  - Antineoplastic Agents: pharmacology
KW  - Proto-Oncogene Proteins c-mdm2: metabolism
KW  - Tumor Microenvironment
KW  - Tumor Suppressor Protein p53 (NLM Chemicals)
KW  - Interleukin-15 (NLM Chemicals)
KW  - Immune Checkpoint Inhibitors (NLM Chemicals)
KW  - Antineoplastic Agents (NLM Chemicals)
KW  - Proto-Oncogene Proteins c-mdm2 (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:37071397
DO  - DOI:10.1158/1541-7786.MCR-22-0898
UR  - https://inrepo02.dkfz.de/record/277908
ER  -