Epigenetic Changes Are the Main Contributor to Immune Escape in Posttransplantation AML Relapse

In patients who relapse after allogeneic hematopoietic stem-cell transplantation, the therapeutic benefits that transplantation provide is diminished through mechanisms that remain unclear. A new study analyzed the genetic and epigenetic alterations of leukemic cells to determine any common features of relapse after transplantation

The down-regulation of major histocompatibility complex (MHC) class II regulatory genes is a frequent cause of the immune escape that leads to posttransplantation acute myeloid leukemia (AML) relapses, according to a study published in New England Journal of Medicine.

Relapse after allogeneic hematopoietic stem-cell transplantation (HSCT) for patients with AML is associated with very poor prognosis. In these patients, the therapeutic benefits that transplantation provide, such as immune-mediated graft-versus-leukemia effect, is diminished through mechanisms that remain unclear. The investigators analyzed the genetic and epigenetic alterations of leukemic cells to determine any common features of relapse after transplantation.

To gather an adequate population pool, investigators enrolled 15 patients who had a relapse of AML after allogeneic HSCT and 20 adult patients who had a relapse of AML after chemotherapy. In the patients who relapsed after transplantation, there were no driver mutations that were found to be associated with relapse after transplantation. The only 2 genes that were found to be mutated in more than 1 patient—ETV6 and FAM98B—were exclusively mutated in 2 patients, and therefore, not being considered a relapse-specific driver mutation. Somatic mutations and structural variants in immune-related genes also were not present in AML after transplantation. There were no gene amplifications in PDL1 and PDL2 as seen in Hodgkin lymphoma, and there were not any recurrent, relapse-specific structural variants such as the MHC class II regulatory gene CIITA.

Because changes in immune-related genes were not observed, investigators speculated that disease progression after AML relapse was due to epigenetic changes in leukemic cells. Compared with patients who relapsed after chemotherapy, where only 8 genes were identified to have changes in expression, patients who relapsed after HSCT had 34 genes that were significantly up-regulated and 187 genes that were significantly down-regulated. One of the down-regulated genes of particular interest was MHC class II gene. Downregulation of this gene diminishes antigen presentation which may contribute to one of the key mechanisms in relapse. In 6 of the 7 patients, there were significantly down-regulated presentations of all the 4 classical MHC class II genes (HLA-DPA1, HLA-DPB1, HLA-DQB1, HLA-DRB1).

To determine if the downregulation of MHC class II genes at relapse was reversible, investigators used interferon-γ to treat 3 cryopreserved patients who relapsed after transplantation. After these cells were treated with interferon-γ, MHC class II proteins were rapidly restored within 72 hours in nearly all AML blasts, indicating that downregulation was mediated through an epigenetic mechanism. Cells treated with interferon-γ were also able to stimulate an immune response, such as activating CD4-positive T cells, compared with cells that were not treated.

From this study, investigators concluded that AML relapses after transplantation were frequently due to epigenetic changes. Because these changes were reversible, re-sensitization strategies may be feasible to promote AML cells to exert graft-versus-leukemia effects after relapse.

Reference

Christopher MJ, Petti AA, Rettig MP, et al. Immune escape of relapsed AML cells after allogeneic transplantation. [published online October 31, 2018]. N Engl J Med. doi: 10.1056/NEJMoa1808777.