| http://purl.uniprot.org/citations/37071397 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
| http://purl.uniprot.org/citations/37071397 | http://www.w3.org/2000/01/rdf-schema#comment | "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.ImplicationsMDM2-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."xsd:string |
| http://purl.uniprot.org/citations/37071397 | http://purl.org/dc/terms/identifier | "doi:10.1158/1541-7786.mcr-22-0898"xsd:string |
| http://purl.uniprot.org/citations/37071397 | http://purl.uniprot.org/core/author | "Brummer T."xsd:string |
| http://purl.uniprot.org/citations/37071397 | http://purl.uniprot.org/core/author | "Duyster J."xsd:string |
| http://purl.uniprot.org/citations/37071397 | http://purl.uniprot.org/core/author | "Duquesne S."xsd:string |
| http://purl.uniprot.org/citations/37071397 | http://purl.uniprot.org/core/author | "Levesque M.P."xsd:string |
| http://purl.uniprot.org/citations/37071397 | http://purl.uniprot.org/core/author | "Becher B."xsd:string |
| http://purl.uniprot.org/citations/37071397 | http://purl.uniprot.org/core/author | "Pfeifer D."xsd:string |
| http://purl.uniprot.org/citations/37071397 | http://purl.uniprot.org/core/author | "Blazar B.R."xsd:string |
| http://purl.uniprot.org/citations/37071397 | http://purl.uniprot.org/core/author | "Giesler S."xsd:string |
| http://purl.uniprot.org/citations/37071397 | http://purl.uniprot.org/core/author | "Turko P."xsd:string |
| http://purl.uniprot.org/citations/37071397 | http://purl.uniprot.org/core/author | "Minguet S."xsd:string |
| http://purl.uniprot.org/citations/37071397 | http://purl.uniprot.org/core/author | "Zeiser R."xsd:string |
| http://purl.uniprot.org/citations/37071397 | http://purl.uniprot.org/core/author | "Andrieux G."xsd:string |
| http://purl.uniprot.org/citations/37071397 | http://purl.uniprot.org/core/author | "Menssen H.D."xsd:string |
| http://purl.uniprot.org/citations/37071397 | http://purl.uniprot.org/core/author | "Wertheimer T."xsd:string |
| http://purl.uniprot.org/citations/37071397 | http://purl.uniprot.org/core/author | "Borries M."xsd:string |
| http://purl.uniprot.org/citations/37071397 | http://purl.uniprot.org/core/author | "Taromi S."xsd:string |
| http://purl.uniprot.org/citations/37071397 | http://purl.uniprot.org/core/author | "Woessner N.M."xsd:string |
| http://purl.uniprot.org/citations/37071397 | http://purl.uniprot.org/core/author | "Braun L.M."xsd:string |
| http://purl.uniprot.org/citations/37071397 | http://purl.uniprot.org/core/author | "Costa-Pereira S."xsd:string |
| http://purl.uniprot.org/citations/37071397 | http://purl.uniprot.org/core/author | "Langenbach M."xsd:string |
| http://purl.uniprot.org/citations/37071397 | http://purl.uniprot.org/core/author | "Richtsfeld S."xsd:string |
| http://purl.uniprot.org/citations/37071397 | http://purl.uniprot.org/core/author | "Rindlisbacher L."xsd:string |