Pyroptosis modulates multiple immune cell populations in targeted therapy–treated melanoma
Menée à l'aide de lignées cellulaires et de modèles murins de mélanome, cette étude met en évidence un mécanisme par lequel la pyroptose induite par la gasdermine E contribue à stimuler la réponse antitumorale de plusieurs populations de cellules immunitaires dans les tumeurs traitées par inhibiteurs de BRAF et inhibiteurs de MEK
Treatment of melanoma with BRAF inhibitors plus MEK inhibitors (BRAFi + MEKi) stimulates an intratumoral immune response, in part through pyroptosis mediated by the pore-forming protein gasdermin E (GSDME/Gsdme). How GSDME mediates effects on tumoral immunity is not well characterized. Using single-cell RNA-sequencing (scRNA-seq) and flow cytometry in BRAFi + MEKi treated melanoma, we show herein that isogenic Gsdme knockout (KO) tumors show decreased infiltration with T cells, natural killer (NK) cells and regulatory T cells (Tregs) compared to control tumors. Infiltrated Tregs in Gsdme KO tumors displayed decreased expression of the interleukin 2 receptor and phenotypic markers associated with suppressive function. Furthermore, intratumoral, the frequency of phenotypically suppressive Tregs were decreased after BRAFi + MEKi treatment in Gsdme KO tumors engineered to express a pyroptosis-defective mutant form of Gsdme (T6E) compared to Gsdme KO tumors engineered to re-express wild-type Gsdme. Combining BRAFi + MEKi with a TLR9 agonist limited regrowth of Gsdme-deficient tumors, and this was associated with a further reduction in intratumoral Tregs. Overall, we show a critical role of GSDME in the modulation of intratumoral immune cells in BRAFi + MEKi-treated melanoma.
Cancer Immunology Research , résumé, 2025