Post-transplantation analyses reveal immune signature changes in relapsed AML.

  • Major Finding: Post-transplantation analyses reveal immune signature changes in relapsed AML.

  • Concept: Upregulation of immune checkpoint ligands and impaired antigen presentation lead to immune evasion in AML.

  • Impact: Therapies tailored on relapse modalities may improve transplantation outcome in AML.

The mainstay treatment regimen for acute myeloid leukemia (AML) is chemotherapy followed by transplantation of hematopoietic cells from healthy donors. The success of transplantation depends on the ability of transferred immune cells to eradicate residual tumor cells to evaluate mechanisms responsible for relapse in patients with AML. Toffalori and colleagues investigated genomic and transcriptomic changes in leukemia collected at diagnosis and post-transplantation relapse from two independent cohorts of 40 and 36 patients, respectively. Differentially expressed genes were identified post-transplantation with significant enrichment in immune-related genes, including alterations in T-cell costimulation and antigen presentation. In the first modality, post-transplantation relapse correlated with downregulation of multiple T-cell costimulatory ligands and upregulation of inhibitory ligands. Analysis of leukemia blasts and T cells collected before and after transplantation revealed an upregulation of immune checkpoint inhibitory molecules such as PD-L1 on blast cells accompanied by an increased percentage of T cells expressing PD-1. Ex-vivo coculture of PD-L1–positive blast cells with PD-1–expressing donor T cells in the presence of anti–PD-L1 led to proliferation of the T cells and IFNγ secretion, illustrating that immune checkpoint blockade may reestablish a proficient graft-versus-tumor effect. A second mechanism of immune evasion involves the transcriptional silencing of HLA class II molecules, resulting in abrogation of CD4 T cell–mediated immune surveillance. Together, these findings demonstrate two novel and alternative nongenomic mechanisms of immune evasion found in patients with post-transplantation relapsed AML. Integrated analysis of the different immune evasion mechanisms predicts that up to two thirds of post-transplantation relapsed cases can be explained by changes in immune patterns. Collectively, these findings provide a rationale for improving outcomes based on each of the identified immune evasion mechanisms, including retransplantation from a different donor for patients with genomic HLA loss, induction of a mild proinflammatory environment in patients with transcriptional silencing of HLA class II, and checkpoint blockade for patients with upregulated inhibitory ligands.

Toffalori C, Zito L, Gambacorta V, Riba M, Oliveira G, Bucci G, et al. Immune signature drives leukemia escape and relapse after hematopoietic cell transplantation. Nat Med 2019;25:603–611.

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