Targeting the mevalonate or Wnt pathways to overcome CAR T-cell resistance in TP53-mutant AML cells

Area of Science:

• Immunology
• Oncology
• Cellular Biology

Background:

• TP53-mutant acute myeloid leukemia (AML) and myelodysplastic neoplasms (MDS) are difficult to treat due to chemotherapy resistance.
• Chimeric antigen receptor (CAR) T-cells show promise for treating these conditions, but their efficacy against TP53-deficient leukemia is unknown.

Purpose of the Study:

• To investigate the impact of TP53 deficiency in AML cells on CAR T-cell efficacy.
• To identify molecular pathways involved in TP53-deficient AML resistance to CAR T-cells.
• To explore therapeutic strategies to enhance CAR T-cell therapy for TP53-mutant AML/MDS.

Main Methods:

• In vitro and in vivo studies comparing CAR T-cell interactions with TP53-deficient versus wild-type AML cells.
• Transcriptional profiling of AML cells and CAR T-cells.
• In vitro validation of targeting the mevalonate and Wnt pathways.

Main Results:

• CAR T-cells showed prolonged interactions, increased exhaustion markers, and reduced killing of TP53-deficient AML cells.
• TP53-deficient AML cells upregulated the mevalonate pathway, while CAR T-cells downregulated the Wnt pathway upon engagement.
• Targeting the mevalonate pathway in AML cells or the Wnt pathway in CAR T-cells restored sensitivity to CAR T-cell-mediated killing.

Conclusions:

• TP53 deficiency in AML confers resistance to CAR T-cell therapy.
• The mevalonate pathway represents a therapeutic vulnerability in TP53-deficient AML cells.
• Wnt pathway modulation offers a strategy to enhance CAR T-cell therapy for TP53-deficient AML/MDS.