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| Home > Publications database > MDM2 Inhibition Enhances Immune Checkpoint Inhibitor Efficacy by Increasing IL15 and MHC Class II Production. |
| Home > Publications database > MDM2 Inhibition Enhances Immune Checkpoint Inhibitor Efficacy by Increasing IL15 and MHC Class II Production. |
| Journal Article | DKFZ-2023-01568 |
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2023
AACR
Philadelphia, Pa.
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Please use a persistent id in citations: doi:10.1158/1541-7786.MCR-22-0898
Abstract: 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.
Keyword(s): Animals (MeSH) ; Mice (MeSH) ; Tumor Suppressor Protein p53: genetics (MeSH) ; Tumor Suppressor Protein p53: metabolism (MeSH) ; Interleukin-15: metabolism (MeSH) ; Interleukin-15: therapeutic use (MeSH) ; Immune Checkpoint Inhibitors: pharmacology (MeSH) ; Immune Checkpoint Inhibitors: therapeutic use (MeSH) ; Cell Line, Tumor (MeSH) ; Melanoma: drug therapy (MeSH) ; Melanoma: genetics (MeSH) ; Antineoplastic Agents: pharmacology (MeSH) ; Proto-Oncogene Proteins c-mdm2: metabolism (MeSH) ; Tumor Microenvironment (MeSH) ; Tumor Suppressor Protein p53 ; Interleukin-15 ; Immune Checkpoint Inhibitors ; Antineoplastic Agents ; Proto-Oncogene Proteins c-mdm2
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