Immune Escape after Allogeneic Hematopoietic Cell Transplantation in Pediatric Acute Myeloid Leukemia.

Overview

Although allogeneic hematopoietic cell transplantation (allo-HCT) is curative for high-risk pediatric acute myeloid leukemia (AML), disease relapse remains the primary cause of post-transplant mortality. To identify pressures imposed by allo-HCT on AML cells that escape the graft-versus-leukemia effect, we evaluated immune signatures at diagnosis and post-transplant relapse in bone marrow samples from four pediatric patients using a multimodal single-cell proteogenomic approach. Downregulation of MHC class II expression was most profound in progenitor-like blasts and accompanied by correlative changes in transcriptional regulation. Dysfunction of activated NK cells and CD8+ T-cell subsets at relapse was evidenced by loss of response to IFN-γ, TNF-α signaling via NF-kβ, and IL-2/STAT5 signaling. Clonotype analysis of post-transplant relapse samples revealed expansion of dysfunctional T cells and enrichment of T-regulatory and T-helper cells. Using novel computational methods, our results illustrate a diverse immune-related transcriptional signature in post-transplant relapses not previously reported in pediatric AML.