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Leukemia Relapse After Stem Cell Transplant Linked to Transcriptional Signature

NEW YORK (GenomeWeb) – Researchers have uncovered a transcriptional signature that is associated with relapse among leukemia patients who have undergone stem cell transplants.

Allogenic hematopoietic celltransplants (allo-HCTs) are a common treatment for leukemia, and while they can lead to a cure, relapses are still frequent among treated patients.

A team led by Luca Vago of the IRCCS San Raffaele Scientific Institute in Milan, Italy, analyzed genomic and gene expression profiles obtained over time from acute myeloid leukemia patients who had undergone transplantation. As they reported today in Nature Medicine, the researchers found a transcriptional signature of post-transplantation relapse that was enriched for immune-related processes. They additionally noted that interferon (IFN)-γ or checkpoint blockade therapy could counteract some of the relapse effects.

"Our results demonstrate that the deregulation of pathways involved in T cell-mediated allorecognition is a distinctive feature and driver of AML relapses after allo-HCT, which can be rapidly translated into personalized therapies," the researchers wrote.

For their discovery cohort, the researchers relied on samples from 40 adult patients who had undergone transplantation for AML and for whom samples had been collected at diagnosis, relapse after chemotherapy, and relapse after allo-HCT. They isolated leukemic cells from these samples and analyzed them using SNP arrays and gene expression arrays.

In a pairwise assessment, the researchers uncovered 110 genes that were differentially expressed between samples taken from patients at diagnosis versus when they relapsed after their stem cell transplant. These were enriched for genes involved in the immune system and could be divvied into two groups: genes associated with T cell co-stimulation and genes linked to antigen processing and presentation using HLA class II molecules.

They noted that activating ligands and adhesion molecules like CD11A/LFA-1 tend to be downregulated in post-transplant relapse samples, while inhibitory ligands are generally unchanged, except for a slight bump in B7-H3 expression.

The researchers confirmed this gene signature in a separate validation cohort of 36 AML patients. For 33 of the patients from their discovery cohort, the researchers also performed an immunophenotypic analysis of their AML blast and T cell samples.

After confirming the changes in B7-H3 and CD11A levels that were indicated by the gene expression analysis, the researchers also noted the upregulation of PD-L1, PVRL2, and CD80 after relapse. In particular, they found that the percentage of T cells expressing PD-1 was higher among AML patients before transplantation, as compared to healthy controls, and that it levels were similarly high in patients in remission and became even higher among post-transplant relapse patients.

This, they, said, suggests that the co-stimulatory interface between T cells and leukemia changes after allo-HCT, with the loss of co-stimulatory interactions like CD28/CD80 and ICAM-1/CD11A and the boosting of inhibitory ones likes PD-1/PD-L1.

In one patient, the researchers found that the expression of PD-1 on donor-derived T cells rose during relapse, but that, in culture, the addition of an anti-PD-L1 blocking antibody led to an increase in the number of donor-derived T cells that could target the patient's leukemic blasts. This, they said, suggests that checkpoint blockade might restore the graft-versus-leukemia effect.

The researchers also noted that post-transplantation relapse patients exhibited downregulation of almost all HLA class II transcripts. When they tested T cells collected from a patient who experienced relapse after a loss of HLA class II expression, they found that this person's T cells responded to the leukemia they had at diagnosis, but not at relapse.

But when exposed to IFN-γ, the leukemia cells exhibited increased HLA class II expression, allowing the T cells to once again target those cells.

This suggested to the researchers that, for many patients, there's an immune pattern that occurs at relapse and could suggest a targeted therapy.