A Study on the Effect of Luspatercept on Regulatory T Cells and Myeloid Derived Suppressor Cells in Low Risk Myelodysplastic Syndrome with Ring Sideroblasts

• Published in: Blood 2024-11, Vol.144, p.1809-1809
• Main Authors: Leone, Stefania, Grimaldi, Francesco, Memoli, Mara, Carriero, Flavia, Scalia, Giulia, Vincenzi, Annamaria, Cerciello, Giuseppe, Pane, Fabrizio, Picardi, Alessandra, Terrazzano, Giuseppe, Ruggiero, Giuseppina, Rubino, Valentina
• Format: Article
• Language: English
• ISSN: 0006-4971
• DOI: 10.1182/blood-2024-210766

In Low-Risk Myelodysplastic Syndromes (LR-MDS), red blood cell transfusion-dependent (RBC-TD) anemia is the primary cause of morbidity and poor outcomes. Luspatecept (Luspa), a recombinant fusion protein that inhibits Smad2/3 signaling induced by TGF-β ligands, is currently approved for the treatment of RBC-TD anemia in LR-MDS with Ring Sideroblasts (LR-MDS-RS). Despite the clinical efficacy of Luspa, its precise mechanism of action is still under investigation. In MDS, immune dysregulation contributes to ineffective hematopoiesis and clonal evolution, with a prominent role played by immune-suppressive populations, primarily represented by Regulatory T-cells (Treg) and Myeloid Derived Suppressive Cells (MDSC). Moreover, Treg-MDSC functional interactions likely involving TGF-B dependent pathways, has been also proposed. By targeting TGF-β signaling pathways, Luspa may indirectly influence the immune microenvironment. Therefore, we aimed to verify if Luspa, by interfering with TGF-β pathway, might affect Treg and MDSCs in patients with LR-MDS-RS. 20 healthy donors and 13 LR-MDS-RS patients with RBC-TD anemia treated with Luspa at Federico II University of Naples have been included in the study from January 2021. Extensive immune profile, including circulating monocyte-MDSC (m-MDSC) and Treg has been performed by multiparametric flow cytometry at baseline and after 6 months of Luspa treatment. Treg were deeply characterized evaluating the expression of the essential transcriptor factor Foxp3 and its highly suppressive isoform containing exon 2 (Foxp3-E2). We performed in vitro experiments to access the ability to Luspa to affect TGF-B dependent Treg induction. No significantly change in the amount of CD4 and CD8 T cells, B cells, NK cells have been observed when compared to HD. We analyzed CD54 expression, as a marker of antigen-dependent T cell activation, on both CD4 and CD8 T cells. In MDS patients, before treatment, we found an increase of CD54 only in CD4 T cell. After Luspa therapy, we found a significantly increase of CD54 in both CD4 and CD8 T cells compared to HD [p