Targeting BLVRB Overcomes Immunosuppression and Potentiates Immunotherapy in Monocytic Acute Myeloid Leukemia
Menée à l'aide de modèles de xénogreffes et d'une analyse multi-omique à l'échelle cellulaire d'échantillons de leucémies myéloïdes aiguës primitives, cette étude met en évidence le caractère immunosuppresseur de la leucémie myéloïde monocytaire et démontre que l'inhibition de l'expression de la biliverdine réductase B (BLVRB) permet de lever l'immunosuppression et d'améliorer l'efficacité des immunothérapies
Acute Myeloid Leukemia (AML) is characterized by significant immunosuppression, limiting the efficacy of immunotherapy. Monocytic AML presents unique immunosuppressive features and constitutes a challenging subtype necessitating focused investigation. Using single-cell multi-omics analyses of primary AML samples, we revealed the immunosuppression landscape of monocytic AML and identified BLVRB as a marker of immunosuppressive monocytic AML cells. BLVRB depletion downregulated immune-modulatory gene expression and sensitized AML cells to T cell cytotoxicity, resulting in improved therapeutic efficacy in cell line and patient-derived xenograft models. Mechanistically, BLVRB signals through the transcription factor MAFB to masterfully promote the expression of various immunosuppression-associated genes, resulting in inhibitory effect against anti-AML T cells. We further demonstrated that the small molecule Tamibarotene targets BLVRB, enhancing the efficacy of both CAR-T and anti-PD-1 antibody therapies in AML. These findings elucidate the critical mechanism regulating immunosuppression in monocytic AML and identify BLVRB as a therapeutic target for improving AML immunotherapy.
Cancer Discovery , résumé, 2026