Abstract
Background:Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that are immunosuppressive and can impair anti-leukemic immune responses in acute lymphoblastic leukemia (ALL). MDSCs are produced in the bone marrow and contribute to the formation of the tumor microenvironment.MDSCs act to suppress both the innate and adaptive responses of antitumor immunity,mostly through direct inhibition of T cell activation and expansion ,including production of a high level of arginase 1(ARG1), inducible nitric oxidase(iNOS) or reactive oxygen species(ROS), as well as indoleamine 2,3-dioxygenase(2,3-IDO) activity. This study analyzed the dynamics of total MDSCs and subsets—polymorphonuclear (PMN-MDSCs), monocytic (M-MDSCs), and early-derived MDSCs—in pediatric B-ALL patients during induction therapy and correlated them with measurable residual disease (MRD), clinical risk, and age.
Methods:
Thirty three newly diagnosed pediatric B cell ALL patients were included in the study after infromed and written consent from the parents and guardians.After baseline line risk stratification induction was initiated using Berlin-frankfurt-Munrich (BFM) regimen in 22 patients (67%) and using ICICLE-ALL-14 regimen in 11 patients(33%).MDSCs were detected by Flow cytometry using a three laser,eight -colour Becton Dickinson(BD) FACS Canto-II Flow cytometer.MRD level of less than or equal to 0.01% is considered as MRD negative .MDSC subsets were quantified among HLA-DR⁻ CD33⁺CD 11b+ lineage⁻ cells. Polymorphonuclear MDSCs are HLA-DR-,CD33+,CD11b+,CD 15+.Monocytic MDSCs are HLA-DR-,CD33+,CD11b+,CD14+.Early-derived MDSCs are HLA-DR-,CD 33+,CD 11b+,CD 14-,CD 15-.Statistical Analysis was done using Wilcoxon signed-rank, Kruskal–Wallis, and Spearman tests.
Results:
This study included 33 patients with a mean age of 7 years (Range: 1 to 18 years).The mean total MDSC proportion (as % of non-debris cellular events) decreased significantly from 1.56% ± 2.29% pre-treatment to 0.392% ± 0.534% post-treatment (p < 0.001).Eighteen males (54.5%) and 15 females (45.5%) were included in the study.MRD negativity was achieved in 25 patients(75.7%) while MRD positivity was seen in 8 patients(24.2%).The number of children that fell in standard risk,intermediate risk and high risk group were 4(12%), 14(42.4%) and 7(21%) respectively.PMN-MDSCs expressed as percentage of total Non-debris cellular events reduced from 0.6% ± 0.8% to 0.1% ± 0.2% (p < 0.001), while M-MDSC level reduction remained statistically unchanged (pretreatment :0.34% ± 0.65%.post treatement 0.30% ± 0.47%).PMN-MDSCs (as % of total MDSCs) declined significantly in both MRD-positive patients from 0.807% pretreatment to 0.078% postvtreatment (p = 0.043) and MRD-negative patients from pretreatment value of 0.596% to post treatment value of 0.090% (p = 0.00066).Early-derived MDSCs were significantly higher pre-treatment in MRD-positive patients (0.4088%) than in MRD-negative patients (0.0575) with statistical significance (p < 0.0001). Post-treatment values of Early-derived MDSC in MRD-negative patients fell to 0.018% and 0.01%, respectively.Risk-stratified analysis showed a gradient of early MDSC burden at baseline: high-risk (0.2114%), intermediate-risk (0.080%), and standard-risk (0.0179%) (p < 0.0001). Corresponding post-treatment values were 0.0157%, 0.0136%, and 0%.No correlation was found between pre-treatment MDSC levels and age (Spearman ρ = 0.002, p = 0.991)
Conclusion:
Induction therapy significantly reduces total and PMN-MDSC populations in pediatric B-ALL. Elevated early-derived MDSCs at diagnosis correlate with MRD positivity and higher clinical risk, supporting their potential as prognostic markers of disease aggressiveness and treatment resistance. These findings underscore the relevance of MDSC subset profiling in pediatric leukemia immunobiology.
