Immune Signature Drives Leukemia Relapse after Transplantation

Transplantation of hematopoietic cells from a healthy individual (allogeneic hematopoietic cell transplantation (allo-HCT)) demonstrates that adoptive immunotherapy can cure blood cancers: still, post-transplantation relapses remain frequent.

A transcriptional signature that is associated with relapse among leukemia patients who have undergone stem cell transplants has been discovered. For many patients, there is an immune pattern that occurs at relapse and could suggest a targeted therapy.

Hematologists and their associates at the IRCCS San Raffaele Scientific Institute (Milan, Italy) used samples from 40 adult patients who had undergone transplantation for acute myeloid leukemia (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 the blast cells using single nucleotide polymorphism (SNP) arrays and gene expression arrays.

The scientists identified a transcriptional signature specific for post-transplantation relapses and highly enriched in immune-related processes, including T cell co-stimulation and antigen presentation. In two independent patient cohorts we confirmed the deregulation of multiple co-stimulatory ligands on AML blasts at post-transplantation relapse (PD-L1, B7-H3, CD80, PVRL2), mirrored by concomitant changes in circulating donor T cells.

After confirming the changes in B7-H3 and CD11A levels that were indicated by the gene expression analysis, the team 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.

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

The authors concluded that their 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 study was published on March 25, 2019, in the journal Nature Medicine.

Related Links:
IRCCS San Raffaele Scientific Institute