The role of the MDM2/p53 axis in antitumor immune responses.

Mouse double minute 2 homolog (MDM2) is a negative regulator of the tumor suppressor p53 and is often highly expressed in acute myeloid leukemia (AML) and other solid tumors. Inactivating mutations in TP53, the gene encoding p53, confers an unfavorable prognosis in AML and increases the risk for relapse after allogeneic hematopoietic cell transplantation. 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 the expression of major histocompatibility complex class I and II, transcription of double stranded RNA of endogenous retroviruses, responses of interferons, production of interleukin-15, and expression of tumor necrosis factor-related apoptosis-inducing ligand receptor 1 and 2 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 antitumor immunity in patients. This review summarizes current evidence supporting the use of MDM2 inhibition to restore p53 as well as the direct effects of MDM2 inhibition on T cells as an emerging concept for combined antitumor immunotherapy against hematological malignancies and beyond.