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

Abstract

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.