Integrating the “Immunome” in the Stratification of Myelodysplastic Syndromes and Future Clinical Trial Design

Abstract

Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis and often include a dysregulation and dysfunction of the immune system. In the context of population aging, MDS incidence is set to increase substantially, with exponential increases in health care costs, given the limited and expensive treatment options for these patients. Treatment selection is mainly based on calculated risk categories according to a Revised International Prognostic Scoring System (IPSS-R). However, although IPSS-R is an excellent predictor of disease progression, it is an ineffective predictor of response to disease-modifying therapies. Redressing these unmet needs, the “immunome” is a key, multifaceted component in the initiation and overall response against malignant cells in MDS, and the current omission of immune status monitoring may in part explain the insufficiencies of current prognostic stratification methods. Nevertheless, integrating these and other recent molecular advances into clinical practice proves difficult. This review highlights the complexity of immune dysregulation in MDS pathophysiology and the fine balance between smoldering inflammation, adaptive immunity, and somatic mutations in promoting or suppressing malignant clones. We review the existing knowledge and discuss how state-of-the-art immune monitoring strategies could potentially permit novel patient substratification, thereby empowering practical predictions of response to treatment in MDS. We propose novel multicenter studies, which are needed to achieve this goal.

Molecular Targeted Therapy in Myelodysplastic Syndromes: New Options for Tailored Treatments

“…Aberrant immune function and dysregulation of immune checkpoint (IC) molecules represent a known pathophysiological aspect of MDS, providing the rationale for studying the role of IC inhibitors (ICI) in those patients, especially after HMA failure [122][123][124].…”

Myelodysplastic Syndromes in the Postgenomic Era and Future Perspectives for Precision Medicine

“…However, it remains unclear whether these are off-target or disease-driving effects. The switch from an activated to exhausted immunological tumor surveillance, referred to as immune subversion, is characteristic for neoplastic conditions and promotes further clonal expansion [30]. Although this immunological phenomenon needs further understanding, it opens the field for early therapeutic interventions aiming to revert immune subversion and reduce progression to higher-risk MDS or sAML.…”

Prognosis in Myelodysplastic Syndromes: The Clinical Challenge of Genomic Integration

“…To holistically understand the complex clinical and biological disease of MDS, a combination of multiomic data that are able to shed light on the relationship between biomolecules, their function, and their coding and modulating components is imperative. As Winter et al recently remarked, the integration of immunome (inflammatory cytokines, genes linked to the inflammasome, cellular responses and bone marrow microenvironment factors) with clinical variables is of particular interest in MDS patients, as more data add relevance to the role of immune dysregulation in MDS pathophysiology [ 68 ].…”