Immune Checkpoint Inhibitors Reverse the Mesenchymal Stromal Cell-Mediated Immunosuppression in Acute Myeloid Leukemia Microenvironment

• Published in: Blood 2024-11, Vol.144, p.4065-4065
• Main Authors: Liu, Rong Xin, Li, Meizhang, Pathak, Harsh B., Lin, Tara L., Skikne, Barry S., McGuirk, Joseph P., Aljitawi, Omar, Godwin, Andrew K., Abdelhakim, Haitham
• Format: Article
• Language: English
• ISSN: 0006-4971
• DOI: 10.1182/blood-2024-208946

Introduction: Acute myeloid leukemia (AML) cells can evade the immune system attack through the support of the bone marrow microenvironment and various cellular and molecular mechanisms. Within the bone marrow microenvironment, mesenchymal stromal cells (MSCs) were identified as a key contributor in promoting AML survival. Furthermore, MSCs can suppress the activity and proliferation of T cells through the expression and secretion of the immune checkpoint ligand, PD-L1. In addition, overexpression of inhibitory checkpoint receptors on CD8+ T cells of AML patients further hints at the critical involvement of the immune checkpoint pathways in AML immune escape. This evidence supports the clinical use of immune checkpoint inhibitors (CPI) in reversing MSC-mediated T cell suppression. However, the role of immune checkpoint inhibitors in AML, specifically for MSC-mediated immune evasion, has not yet been firmly established. We hypothesize that 1) bone marrow MSCs assist AML cells evading the T cell attack through the overexpression of inhibitory immune checkpoints, and 2) MSC-mediated T cell suppression could be reversed using CPI. Methods: In this study, we established a 3-dimensional (3D) biomimetic model of decellularized Wharton's jelly matrix and primary AML patient samples to simulate the bone marrow microenvironment and the interplay between AML cells, MSCs, and T cells. The MSCs were isolated and expanded from the bone marrow mononuclear cells of each AML patient (n=4) to be used for the 3D model development. The AML cells and PBMCs for each of the corresponding patient were seeded in the presence or absence of MSCs and incubated for 1 day to assess the level of AML killing and the level of T cell activation using a far red-labeled AML cell-based killing assay and flow cytometry of intracellular cytokines (IFNγ, TNFα), respectively. An identical experimental set up was incubated for 3 days for immunophenotypic characterization of the surface markers (AML cells: CD33, CD34, HLA-ABC, PD-L1; CD8+ T cells: CD3, CD4, CD8, PD-1, LAG-3, TIM-3) using flow cytometry. With the established 3D model, the effect of CPI (bispecific anti-PD-1 x anti-LAG-3 DART®molecule, MGD013/tebotelimab; anti-LAG-3 IgG4 antibody; and anti-PD-1 IgG4 antibody, nivolumab) on AML killing and T-cell activity were assessed and compared to a palivizumab-based IgG4 antibody as a control. The DART molecule and antibodies, except for nivolumab, were provided by MacroGenics, Inc., MD, USA. Res