Interferon-Gamma Production By Dysplastic Cells Supports an Immune-Tolerant Bone Marrow Microenvironment in Myelodysplastic Syndrome Patients

Background: Myelodysplastic syndromes (MDS) are a heterogeneous group of haematological malignancies with a poor prognosis and a risk of evolving into acute myeloid leukaemia (AML). Besides intrinsic cellular defects, extrinsic microenvironmental factors, particularly inflammatory signals in the bone marrow (BM), play a crucial role in MDS progression.

In AML, we demonstrated that leukemic cells produced interferon (IFN)γ, allowing us to stratify them in INFGhigh and IFNGlow samples. Higher IFNγ levels remodelled the BM microenvironment, favouring the indoleamine 2,3-dioxygenase (IDO)1-dependent induction of immunosuppressive Tregs associated with increased engraftment of leukemic cells in a mouse model. Furthermore, AML samples with increased IFNγ production showed downregulated expression of HLA class II genes, including CIITA (Class II major histocompatibility complex transactivator). Since leukemic cells with high CIITA methylation are resistant to HLA-dependent IFNγ up-regulation, CIITA methylation/HLA-downregulation could represent a further IFNγ-dependent mechanism of immune suppression. This study aims to explore Tregs induction and HLA down-regulation as putative IFNγ-dependent mechanisms of tolerance and immune escape in MDS, eventually favouring AML progression.

Methods: We used quantitative real-time PCR and flow cytometry to characterize BM-derived MDS samples (N=22) at diagnosis.

Results: MDS samples showed varying IFNγ levels, generally higher than in AML samples. MDS samples had more IFNγ-positive cells in the BM than IFNGlow AML samples, with dysplastic cells being the primary source of IFNγ, although CD3⁺, CD8⁺ T cells, and NK cells also contributed. Interestingly, we found a positive correlation between IFNγ and IDO1 expression at both mRNA and protein levels, suggesting an immune-tolerant microenvironment in MDS similar to AML.

Next, MDS samples had a higher percentage of total Tregs than healthy donors and IFNGlow AML samples but lower than INFGhigh AML samples. Treg levels varied with MDS prognostic risk. MDS samples also exhibited different levels and patterns of HLA class II gene expression correlated with IFNγ, with some MDS samples holding an IFNγ-inducible HLA class II gene expression and others with a not-inducible HLA class II gene expression, suggesting a correlation with CIITA methylation grade.

Summary/Conclusions:

This study shows that IFNγ production by MDS cells remodels the BM landscape toward IDO1 upregulation, Treg induction and modulation of HLA class II gene expression, supporting the immune-tolerant role of inflammation, which is emerging as a critical aspect in AML prognosis and outcome and could be implied in MDS risk stratification and progression in AML.

Curti:Pfizer: Honoraria, Research Funding; Abbvie: Honoraria; Jazz Pharmaceutics: Honoraria; Menarini stemline: Honoraria.