Somatic TP53 Mutations Drive T and NK Cell Dysfunction in AML and Can be Rescued by Reactivating Wild Type p53.

Area of Science:

• Oncology
• Immunology
• Genetics

Background:

• Immunotherapy has improved outcomes for lymphomas and myelomas.
• TP53-mutant acute myeloid leukemia (AML) remains a therapeutic challenge.
• The role of TP53 mutations in immune cells of AML patients is largely unknown.

Purpose of the Study:

• To investigate the presence and functional impact of TP53 mutations in immune cells from AML patients.
• To explore the consequences of TP53 mutations on T-cell function and CAR-T cell therapy.
• To evaluate p53 reactivation as a therapeutic strategy for TP53-mutant AML.

Main Methods:

• Single-cell multi-omics and phenotypic analyses were used to identify TP53 mutations in T and NK cells.
• Chimeric antigen receptor T (CAR-T) cells engineered with TP53 mutations were created to assess functional consequences.
• In vitro and in vivo (PDX mouse models) experiments were conducted to evaluate CAR-T cell function and therapeutic efficacy.
• A small-molecule p53 reactivator was used to assess its ability to restore function in mutant p53 CAR-T cells.

Main Results:

• TP53 mutations were identified in T and NK cells of AML patients.
• TP53-mutant T cells showed reduced cytotoxicity and increased exhaustion markers (PD-1, TIGIT, TIM-3).
• Engineered mutant p53 CAR-T cells exhibited impaired cytokine secretion and tumor lysis, demonstrating a pronounced exhaustion phenotype.
• p53 reactivation rescued CAR-T cell functionality, reduced exhaustion markers, and improved survival in AML models.

Conclusions:

• TP53-mutant T cells are a novel driver of immune escape in AML.
• Targeting TP53 mutations in immune cells is crucial for overcoming therapeutic resistance in AML.
• Selective p53 reactivation presents a promising therapeutic avenue for TP53-mutant AML immunotherapy.