MDM2 inhibition enhances immune checkpoint inhibitor efficacy by increasing IL-15 and MHC class II production

The treatment of metastatic melanoma patients with immune checkpoint inhibitors (ICI) leads to impressive response rates but primary and secondary resistance to ICI reduce 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 IL-15 and MHC-II in murine melanoma cells upon p53 induction by MDM2-inhibition. MDM2-inhibitor induced MHC-II and IL-15-production, which was p53 dependent as p53 knockdown blocked the effect. Lack of IL-15-receptor in hematopoietic cells or IL-15 neutralization reduced the MDM2-inhibition/p53-induction mediated anti-tumor 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 IL-15 and MHC-II. IL-15 and CIITA expression was associated with a more favorable prognosis in patients bearing WT but not TP53 mutated melanoma. Implications: MDM2-inhibition represents a novel strategy to enhance IL-15 and MHC-II-production, which disrupts the immunosuppressive tumor microenvironment. Based on our findings a clinical trial combining MDM2-inhibition with anti-PD-1 immunotherapy for metastatic melanoma is planned.