Dendritic Cells of Leukemic Origin (DCleu) Modulate the Expression of Inhibitory Checkpoint Molecules and Their Ligands on T Cells and Blasts in AML Relapse After Allogeneic Stem Cell Transplantation.

Background

Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a potentially curative treatment for high-risk acute myeloid leukemia and myelodysplastic neoplasms (AML/MDS). However, AML/MDS relapse post-transplant is driven by immune escape mechanisms, limiting treatment options and contributing to poor prognosis. Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) and Prostaglandin-E1 (PGE-1) (termed "Kit M") induce dendritic cells of leukemic origin (DCleu) that have been shown to induce antileukemic immune responses.

Methods

Using flow cytometry, we analyzed ICM/ICML-expressing uncultured T-cells/blasts in whole blood (WB) samples from patients with AML/MDS relapse post-allo-HCT who had received salvage treatment. Using Kit M, DCleu were generated ex vivo. T-cell-enriched mixed-lymphocyte cultures (MLC) were performed for functional assessment of DC/DCleu to stimulate (leukemia specifically) patients' immune cells. After MLC, ICM/ICML-expressing cells and immune activation were assessed. The experimental results were correlated with patients' clinical responses to salvage treatment.

Results

WB samples from 15 patients were analyzed. On average, high frequencies of ICM (CTLA4/PD1)-co-expressing blasts and high frequencies of ICM (CTLA4/PD1/TIGIT/TIM3/2B4)-co-expressing T-cells were found in uncultured WB, compared to the frequencies of healthy ICM-expressing T-cells. Treatment with Kit M induced DC/DCleu, which, after MLC, downregulated ICM-expressing T-cells and enhanced activated and memory T-cells. High frequencies of ICM-co-expressing uncultured T-cells/blasts correlated negatively with the blast lysis capacity and patients' clinical response to relapse treatment. However, post-MLC, Kit-mediated modulation of ICM-expressing T cells did not correlate with blast lysis, nor with patients' clinical response to treatment.

Conclusions

We conclude that Kit M contributes to overcoming impaired antileukemic reactions, independent of the presence of ICM-expressing T-cells in relapsed AML patients after allo-HCT ex vivo.