MDM2 Inhibition Enhances Immune Checkpoint Inhibitor Efficacy by Increasing IL15 and MHC Class II Production

• Published in: Molecular cancer research 2023-08, Vol.21 (8), p.849-864
• Main Authors: Langenbach, Marlene, Giesler, Sophie, Richtsfeld, Stefan, Costa-Pereira, Sara, Rindlisbacher, Lukas, Wertheimer, Tobias, Braun, Lukas M, Andrieux, Geoffroy, Duquesne, Sandra, Pfeifer, Dietmar, Woessner, Nadine M, Menssen, Hans D, Taromi, Sanaz, Duyster, Justus, Börries, Melanie, Brummer, Tilman, Blazar, Bruce R, Minguet, Susana, Turko, Patrick, Levesque, Mitchell P, Becher, Burkhard, Zeiser, Robert
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Immune Checkpoint Inhibitors - pharmacology; Immune Checkpoint Inhibitors - therapeutic use; Interleukin-15 - metabolism; Interleukin-15 - therapeutic use; Melanoma - drug therapy; Melanoma - genetics; Mice; Proto-Oncogene Proteins c-mdm2 - metabolism; Tumor Microenvironment; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism
• ISSN: 1541-7786; 1557-3125
• DOI: 10.1158/1541-7786.MCR-22-0898

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.