Anti-BCL2 therapy eliminates giant congenital melanocytic nevus by senolytic and immune induction

Area of Science:

• Dermatology
• Oncology
• Immunology

Background:

• Giant congenital melanocytic nevus (GCMN) presents significant challenges due to extensive lesions and malignancy risk.
• Current treatments like surgery and laser therapy are insufficient, and MAPK inhibitors have limited efficacy.
• GCMN lesions contain both senescent and proliferative cells, requiring multifaceted therapeutic approaches.

Purpose of the Study:

• To investigate novel therapeutic strategies for GCMN targeting cellular senescence and survival pathways.
• To evaluate the efficacy of BCL2 inhibitors (BCL2i) alone and in combination with immune responses in GCMN models.
• To elucidate the role of the immune system in GCMN regression following targeted therapy.

Main Methods:

• Analysis of senescent and proliferative cell populations in GCMN samples.
• In vitro cytotoxicity assays of BCL2 inhibitors on GCMN cells.
• In vivo studies using patient-derived xenografts and transgenic mouse models (NrasQ61K, BrafV600E).
• Assessment of immune cell infiltration, neutrophil extracellular traps (NETs), and T cell responses post-treatment.

Main Results:

• BCL2 is expressed in both senescent and proliferative GCMN cells, indicating its potential as a therapeutic target.
• BCL2 inhibitors demonstrated significant cytotoxicity against GCMN cells in vitro.
• BCL2i treatment led to GCMN lesion clearance and hypopigmentation in preclinical models.
• Immune cell infiltration, particularly activated neutrophils forming NETs, was crucial for BCL2i efficacy.
• Neutrophil depletion or immunosuppression diminished treatment effectiveness, highlighting the immune system's role.

Conclusions:

• Targeting BCL2 offers a promising therapeutic avenue for GCMN by inducing cell death and synergizing with the immune system.
• The combination of BCL2 inhibition and immune activation, particularly involving neutrophils, effectively treats GCMN.
• Long-term follow-up suggests durable responses and the establishment of immune memory, preventing recurrence.