Inhibition of MDM2 promotes anti-tumor responses in p53 wild-type cancer cells through their interaction with the immune and stromal microenvironment

p53 is a transcription factor that plays a central role in guarding the genomic stability of cells through cell cycle arrest or induction of apoptosis. However, the effects of p53 in anti-tumor immunity are poorly understood. To investigate the role of p53 in controlling tumor-immune cell crosstalk, we studied murine syngeneic models treated with HDM201, a potent and selective second generation MDM2 inhibitor. In response to HDM201 treatment, the percentage of dendritic cells (DC) increased, including the CD103+ antigen cross-presenting subset. Furthermore, HDM201 increased the percentage of Tbet+Eomes+ CD8+ T cells and the CD8/Treg ratio within the tumor. These immunophenotypic changes were eliminated with the knockout of p53 in tumor cells. Enhanced expression of CD80 on tumor cells was observed in vitro and in vivo, which coincided with T-cell mediated tumor cell killing. Combining HDM201 with PD-1 or PD-L1 blockade increased the number of complete tumor regressions. Responding mice developed durable, antigen-specific memory T cells and rejected subsequent tumor implantation. Importantly, anti-tumor activity of HDM201 in combination with PD-1/PD-L1 blockade was abrogated in p53-mutated and knockout syngeneic tumor models, indicating the effect of HDM201 on the tumor is required for triggering anti-tumor immunity. Taken together, these results demonstrate that MDM2 inhibition triggers adaptive immunity, which is further enhanced by blockade of PD-1/PD-L1 pathway, thereby providing a rationale for combining MDM2 inhibitors and checkpoint blocking antibodies in patients with wild-type p53 tumors.