The role of the MDM2/p53 axis in anti-tumor immune responses

Abstract

Mouse double minute 2 homolog (MDM2) is a negative regulator of the tumor suppressor p53 and often highly expressed in acute myeloid leukemia (AML) and different solid tumors. Inactivating mutations in TP53, the gene encoding for p53, confers an unfavorable prognosis in AML and increases the risk for relapse after allogeneic hematopoietic cell transplantation (allo-HCT). We review the concept that manipulation of MDM2 and p53 could enhance immunogenicity of AML and solid tumor cells. Additionally, we discuss the mechanisms by which MDM2 and p53 regulate MHC class I and II expression, transcription of dsRNA of endogenous retroviruses, interferon responses, IL-15 production and TRAIL-receptor 1 and 2 expression on malignant cells. The direct effects of MDM2-inhibition or MDM2 deletion in effector T cells are discussed in the context of cancer immunotherapy. The preclinical findings are connected to clinical studies using MDM2-inhibition to enhance anti-tumor immunity in patients. In aggregate, this review summarizes current evidence supporting the use of MDM2-inhibition to restore p53, as well as direct effects of MDM2-inhibition on T cells as an emerging concept for combined anti-tumor immunotherapy against hematological malignancies and beyond.