Immune-monitoring of myelodysplastic neoplasms: Recommendations from the i4MDS consortium

Abstract

Advancements in comprehending myelodysplastic neoplasms (MDS) have unfolded significantly in recent years, elucidating a myriad of cellular and molecular underpinnings integral to disease progression. While molecular inclusions into prognostic models have substantively advanced risk stratification, recent revelations have emphasized the pivotal role of immune dysregulation within the bone marrow milieu during MDS evolution. Nonetheless, immunotherapy for MDS has not experienced breakthroughs seen in other malignancies, partly attributable to the absence of an immune classification that could stratify patients toward optimally targeted immunotherapeutic approaches. A pivotal obstacle to establishing "immune classes" among MDS patients is the absence of validated accepted immune panels suitable for routine application in clinical laboratories. In response, we formed International Integrative Innovative Immunology for MDS (i4MDS), a consortium of multidisciplinary experts, and created the following recommendations for standardized methodologies to monitor immune responses in MDS. A central goal of i4MDS is the development of an immune score that could be incorporated into current clinical risk stratification models. This position paper first consolidates current knowledge on MDS immunology. Subsequently, in collaboration with clinical and laboratory specialists, we introduce flow cytometry panels and cytokine assays, meticulously devised for clinical laboratories, aiming to monitor the immune status of MDS patients, evaluating both immune fitness and identifying potential immune "risk factors." By amalgamating this immunological characterization data and molecular data, we aim to enhance patient stratification, identify predictive markers for treatment responsiveness, and accelerate the development of systems immunology tools and innovative immunotherapies.

Figure 1

Flow diagram for literature review regarding immune cell type alterations in myelodysplastic neoplasms.

Figure 2

Immune and bone marrow environment changes during the MDS course. Main alterations in low‐risk, high‐risk, or all MDS patients are specified in red, blue, and black, respectively. DC, dendritic cell; IL, interleukin; Ly, lymphocyte; MDS, myelodysplastic neoplasms; MDSC, myeloid‐derived suppressor cell; MSC, mesenchymal stromal cell; NK, natural killer; Th, Helper CD4⁺ T cell; Treg, regulatory T cell. Dashed lines represent impaired differentiation.

Figure 3

Multiomics modeling pipeline to integrate the assessment of the immune signature in myelodysplastic neoplasms.

Figure 4

Patients screening for immune signature evaluation. ANC, absolute neutrophile count; CCUS, clonal cytopenia of unknown significance; Hb, hemoglobin; ICUS, idiopathic cytopenia of unknown significance; MNC, mononuclear cells; PLT, platelets.

Figure 5

Cell markers to identify cell subtypes from the International Integrative Innovative Immunology for MDS panel (optional markers in red). *Functional assay is necessary for definite identification of myeloid‐derived suppressor cells.