Immunological biomarkers and TARC/CCL17 in myelodysplastic syndrome: Insights into immune microenvironment regulation

Abstract Background: Immune dysregulation is central to myelodysplastic syndrome (MDS) pathogenesis, with inflammatory cytokines and chemokines implicated in disease progression. Thymus and activation-regulated chemokine (TARC/CCL17) orchestrates immune tolerance by recruiting CCR4+ regulatory T cells and Th2 cells, creating immunosuppressive microenvironments that facilitate clonal expansion. Likewise, proinflammatory cytokines such as TNF-α, IL-6, IFN-γ, and chemokines including CCL5 and CXCL10 have been implicated in MDS-related immune dysregulation and ineffective hematopoiesis. While TARC/CCL17 serves as a prognostic biomarker in lymphomas, its role within the broader cytokine milieu of MDS remains unexplored. Methods: We analyzed 52 treatment-naive MDS patients stratified by revised International Prognostic Scoring System (IPSS-R) and Molecular IPSS (IPSS-M): 15 intermediate-high risk, 37 low-risk, plus 30 age-matched healthy controls. Using ELISA methodology, we quantified serum levels of TARC/CCL17, CCL5, CXCL10, interleukin (IL)-6, IL-10, interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α). Clinical parameters including transfusion dependence, blast burden, and cytogenetic risk were correlated with biomarker profiles using non-parametric testing with Bonferroni correction. Results: Intermediate-high risk patients demonstrated expected disease characteristics: higher blast percentages (20% vs 2.7% with ≥5% blasts, p<0.0001), increased transfusion requirements (73.3% vs 21.6%, p=0.0006), and elevated ferritin (median 497 vs 116 ng/mL, p=0.011). Comprehensive immune profiling revealed no significant differences in any measured cytokines between MDS patients and controls. TARC/CCL17 levels showed similar medians: 456.47 pg/mL (intermediate-high risk), 439.64 pg/mL (low-risk), and 513.97 pg/mL (controls; p=0.289). Similarly, TNF-α, IL-6, IFN-γ, CCL5, and CXCL10 showed no significant variance between cohorts (all p>0.05). Subgroup analysis by cytogenetic risk, transfusion status, and blast percentage confirmed absence of systemic immune activation patterns. Conclusions: Despite established evidence implicating immune dysregulation in MDS pathogenesis, circulating cytokines and chemokines—including TARC/CCL17—showed no significant differences between patients and controls. This challenges the prevailing notion that peripheral biomarkers adequately reflect MDS immune landscape. The absence of systemic immune activation likely reflects compartmentalized signaling confined to the bone marrow niche, which peripheral assays fail to capture. Previous treatments, disease heterogeneity, and temporal immune dynamics across risk categories may contribute to undetectable systemic changes. These findings underscore limitations of peripheral biomarkers in assessing MDS immune activity and advocate for tissue-specific approaches such as bone marrow immunophenotyping. Future studies integrating localized cytokine mapping with molecular profiling may provide superior tools for immune-targeted therapy development.