Mechanisms of Leukemia Immune Evasion and Their Role in Relapse After Haploidentical Hematopoietic Cell Transplantation

Pier Edoardo Rovatti, Valentina Gambacorta, Francesca Lorentino, Fabio Ciceri, Luca Vago, Pier Edoardo Rovatti, Valentina Gambacorta, Francesca Lorentino, Fabio Ciceri, Luca Vago

Abstract

Over the last decade, the development of multiple strategies to allow the safe transfer from the donor to the patient of high numbers of partially HLA-incompatible T cells has dramatically reduced the toxicities of haploidentical hematopoietic cell transplantation (haplo-HCT), but this was not accompanied by a similar positive impact on the incidence of post-transplantation relapse. In the present review, we will elaborate on how the unique interplay between HLA-mismatched immune system and malignancy that characterizes haplo-HCT may impact relapse biology, shaping the selection of disease variants that are resistant to the "graft-vs.-leukemia" effect. In particular, we will present current knowledge on genomic loss of HLA, a relapse modality first described in haplo-HCT and accounting for a significant proportion of relapses in this setting, and discuss other more recently identified mechanisms of post-transplantation immune evasion and relapse, including the transcriptional downregulation of HLA class II molecules and the enforcement of inhibitory checkpoints between T cells and leukemia. Ultimately, we will review the available treatment options for patients who relapse after haplo-HCT and discuss on how a deeper insight into relapse immunobiology might inform the rational and personalized selection of therapies to improve the largely unsatisfactory clinical outcome of relapsing patients.

Keywords: HLA; haploidentical allogeneic hematopoietic stem cell transplantation; immune check point; immune escape; relapse.

Copyright © 2020 Rovatti, Gambacorta, Lorentino, Ciceri and Vago.

Figures

Figure 1
Figure 1
Tumor-Intrinsic Mechanisms of Immune Evasion and Relapse. This cartoon summarizes the features of the three modalities of leukemia immune evasion and relapse after allo-HCT better characterized to date. Chromosomes indicate the HLA haplotype homo- or hetero-zygosity, showing in cyan the donor-recipient shared haplotype and in red the patient-specific incompatible haplotype. The padlock symbolizes epigenetic silencing of the HLA class II loci. On the cell surface, HLA class I molecules are shown as heterodimers of HLA and beta-2-microglobulin (in yellow), HLA class II as dimers of two transmembrane single-chain HLA molecules, and inhibitory ligands as green homodimers.
Figure 2
Figure 2
Tumor-Extrinsic Mechanisms of Immune Evasion and Relapse. This cartoon summarizes several of the pathways exploited by leukemic cells in order to rewire the bone marrow microenvironment and evade immune recognition. In particular, featured in the figure are the deregulated release by AML blasts of cytokines, such as interferon-γ (IFN-γ), interleukin-15 (IL-15), and granulocyte-colony stimulating factor (G-CSF); the expression of enzymes involved in aminoacid metabolism, such as arginase (Arg) and indoleamine 2,3-dioxygenase (IDO-1); and the upregulation of the ectonucleotidases CD73 and CD39 that leads to the increase in extracellular adenosine (ADO). All of these mediators can have an impact on the frequency and function of immune cell subsets, impairing T and NK cell activity, driving effector T cells toward exhaustion, inducing the expansion of regulatory T cells (Treg), and promoting the phenotypic switch of macrophages from pro-inflammatory M1 to immuno-suppressive M2.

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