Issues

In addition to its tumor suppressor gene function, p53 has been shown to contribute to silencing of repetitive elements including endogenous retrovirus (ERV) long terminal repeat sequences. Zhou, Singh, and colleagues made the unexpected observation that upon p53 activation through pharmacologic inhibition of its negative regulator MDM2, ERV expression was increased due to increased p53 occupancy on ERV promoters and p53-mediated suppression of LSD1 and DNMT1, two major ERV repressors. ERV derepression following MDM2 inhibition contributed to double-stranded RNA stress leading to type I/III interferon (IFN) expression, antigen processing/presentation, and increased T-cell infiltration. Additionally, dual treatment with an anti–PD-1 antibody along with an MDM2 inhibitor markedly reduced tumor growth in a poorly immunogenic murine model of melanoma as compared with checkpoint therapy alone. An augmentation of IFN signaling and immune cell recruitment was also observed in patients who received an MDM2 inhibitor. For more information, see the article by Zhou, Singh, and colleagues on page 3090.