Pyroptosis Modulates Multiple Immune Cell Populations in Targeted Therapy-Treated Melanoma

Area of Science:

• Immunology
• Oncology
• Cell Biology

Background:

• BRAF inhibitors plus MEK inhibitors (BRAFi + MEKi) enhance anti-melanoma immunity via pyroptosis, a cell death process mediated by gasdermin E (GSDME).
• The precise mechanisms by which GSDME influences tumor immunity remain incompletely understood.

Purpose of the Study:

• To investigate the role of GSDME in modulating the intratumoral immune microenvironment during BRAFi + MEKi treatment for melanoma.
• To elucidate how GSDME affects immune cell infiltration and function, particularly regulatory T cells (Tregs).

Main Methods:

• Single-cell RNA-sequencing (scRNA-seq) and flow cytometry were employed on melanoma models.
• Gsdme knockout (KO) and engineered Gsdme mutant melanoma models were utilized.
• BRAFi + MEKi treatment, alone and in combination with a TLR9 agonist, was administered.

Main Results:

• Gsdme KO tumors exhibited reduced infiltration of T cells, NK cells, and Tregs compared to control tumors.
• Tregs within Gsdme KO tumors showed diminished expression of the interleukin-2 receptor and suppressive markers.
• Melanoma treatment with BRAFi + MEKi combined with a TLR9 agonist suppressed tumor regrowth and further decreased intratumoral Tregs in Gsdme-deficient models.

Conclusions:

• GSDME plays a critical role in orchestrating the intratumoral immune response in melanoma treated with BRAFi + MEKi.
• GSDME-mediated pyroptosis is essential for optimal T cell and NK cell infiltration and for reducing the suppressive function of Tregs.
• Targeting GSDME or enhancing its function may represent a therapeutic strategy to improve responses to BRAFi + MEKi therapy in melanoma.