IMMUNO-PROFILING OF PEDIATRIC COHORT OF PATIENTS AFFECTED BY ACUTE LYMPHOBLASTIC LEUKEMIA IN THE MIDDLE EAST: STEP TOWARDS PRECISION MEDICINE

Abstract

Background: Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer with its tumor microenvironment (TME) playing a significant role in the disease’s progression and response to treatment. Most of the studies related to ALL TME focused on the role of single or two components within the TME. However, less is known about the dynamic interplay between the diverse cellular components and soluble mediators (cytokines) at the different treatment phases. This study aims to investigate the interplay between three key immune cell subsets, myeloid derived suppressor cells (MDSCs), regulatory T-cells (Tregs), and Helper T-cells (Ths), and cytokine profile within the TME of pediatric ALL patients. Methods: Bone marrow (BM) and/or peripheral blood (PB) samples were collected from a cohort of pediatric ALL patients (n=16) at diagnosis (D0), during treatment (D33, D78, and/or D92), at relapse, and/or relapse time point 3 (R-TP3). A reference group of pediatric heathy donors (HDs) (n=8) was used. High dimensional flow cytometry panels (up to 20-color) were used to evaluate the levels of 10 MDSC subtypes, Tregs, and 5 Th subtypes at different time points. Cytokine profiling was performed using 48-Plex multiplex assay in a format of 384-well plate. Results: MDSC8 and MDSC9 demonstrated an increasing trend across the time points, with the highest level at relapse. In contrast, Th1 and Th17 cells showed a decreasing trend throughout the treatment time points, suggesting an immunosuppressive shift in the TME. Tregs fluctuated across time points. Comparison between the three immune cell subsets revealed an inverse relationship between MDSC levels and both Th1 and Th17. Cytokine profiling showed imbalance in pro- and anti-inflammatory immunological mediators. For instance, interferon-Ƴ (IFN-Ƴ) and tumor necrosis factor-α (TNF-α) were consistently elevated compared to HDs, while interleukin-12 (IL-12), IL-1β, and IL-2 were low. Conclusion: Our study suggested dynamic immune remodeling in the TME of pediatric ALL, with a shift toward immunosuppressive TME during treatment and relapse. The increase in MDSCs and decrease in Th1 and Th17 levels might reflect mechanisms of immune escape. Our findings provide significant insights into pediatric ALL progression and potential discovery of novel biomarkers for personalized therapy.

Date of Award	2025
Original language	American English
Awarding Institution	HBKU College of Health & Life Sciences