Relapse of acute myeloid leukemia after allogeneic stem cell transplantation: immune escape mechanisms and current implications for therapy

Abstract

Acute myeloid leukemia (AML) is a heterogeneous disease characterized by the expansion of immature myeloid cells in the bone marrow (BM) and peripheral blood (PB) resulting in failure of normal hematopoiesis and life-threating cytopenia. Allogeneic hematopoietic stem cell transplantation (allo-HCT) is an established therapy with curative potential. Nevertheless, post-transplant relapse is common and associated with poor prognosis, representing the major cause of death after allo-HCT. The occurrence of relapse after initially successful allo-HCT indicates that the donor immune system is first able to control the leukemia, which at a later stage develops evasion strategies to escape from immune surveillance. In this review we first provide a comprehensive overview of current knowledge regarding immune escape in AML after allo-HCT, including dysregulated HLA, alterations in immune checkpoints and changes leading to an immunosuppressive tumor microenvironment. In the second part, we draw the line from bench to bedside and elucidate to what extend immune escape mechanisms of relapsed AML are yet exploited in treatment strategies. Finally, we give an outlook how new emerging technologies could help to improve the therapy for these patients, and elucidate potential new treatment options.

Keywords: Acute myeloid leukemia; Allogeneic stem cell transplantation; Human leukocyte antigen; Immune checkpoints; Immune escape; Relapse; Therapeutic options.

Fig. 1

Overview of immune escape mechanisms in AML after allogeneic stem cell transplantation. The various immune evasion strategies include genomic loss or downregulation of HLA (1), upregulation of inhibitory or downregulation of activating receptors and the corresponding ligands (2), exhausted and dysfunctional immune effector cells (3a), an altered metabolic environment (3b) as well as an increase of immunosuppressive cell types (MDSCs, M2 macrophages and TAMs, T regs) and vascular remodelling of the AML niche cells (3c). This figure was created using Biorender. ¹ Recent studies indicate that epigenetic downregulation could also affect HLA class I [26]. AML blast: acute myeloid leukemia blast, LSC: Leukemic stem cell, DC: dendritic cell, NK cell: Natural killer cell, MSC: mesenchymal stem cell, MDSC: myeloid derived suppressor cell, TAM: tumor associated macrophage. ↑ indicates upregulation, whereas ↓ marks downregulation