MDM2 inhibition enhances immune checkpoint inhibitor therapy in melanoma

Immune checkpoint therapy has improved outcome of patients with advanced melanoma, however the tumor becomes refractory in a large number of patients. Therefore, novel combination therapies that enhance anti-melanoma immunity are highly desirable. We studied the impact of MDM2 (mouse double minute 2) inhibition, leading to p53 activation, on response to anti-PD-1 immunotherapy in melanoma. MDM2 treatment caused upregulation of MHC II and IL-15 in melanoma cells in a p53 dependent manner. Survival of melanoma bearing mice improved upon combining anti-PD1 and MDM2 inhibition in vivo. Lack of IL-15Rα in T cells abrogated the beneficial effect of the combined treatment. This gene expression study was performed to determine potential effects of MDM2 inhibition on genes in the melanoma microenvironment. Melanoma cells were subcutaneously injected into five mice, which were treated with anti-PD1. Every other day, two mice were treated with vehicle and three mice were treated with MDM2 inhibitor. The tumors were excised on day 13 and total RNA was isolated. For the gene expression study, a total of five samples were analysed, two of which were control samples from vehicle-treated mice and the other three samples were obtained from the mice treated with MDM2 inhibitor.