Abstract
In human leukocyte antigen (HLA)-matched stem cell transplantation (SCT), it has been shown that beneficial immune response mediating graft-versus-tumor (GVT) responses can be separated from graft-versus-host disease (GVHD) immune responses. In this study, we investigated whether it would be possible to dissect the beneficial immune response of allo-HLA-reactive T cells with potent antitumor reactivity from GVHD-inducing T cells present in the detrimental immune response after HLA-mismatched SCT. The presence of specific tumor-reactive T cells in the allo-HLA repertoire was analyzed at the time of severe GVHD after HLA-mismatched SCT, using tetramers composed of different tumor-associated antigens (TAA). High-avidity allo-HLA-restricted T cells specific for the TAA preferentially expressed antigen on melanomas (PRAME) were identified that exerted highly single-peptide-specific reactivity. The T cells recognized multiple different tumor cell lines and leukemic cells, whereas no reactivity against a large panel of nonmalignant cells was observed. These T cells, however, also exerted low reactivity against mature dendritic cells (DC) and kidney epithelial cells, which was shown to be because of low PRAME expression. On the basis of potential beneficial specificity and high reactivity, the T-cell receptors of these PRAME-specific T cells may be effective tools for adoptive T-cell therapy. Clinical studies have to determine the significance of the reactivity observed against mature DCs and kidney epithelial cells.
Highlights
Alloreactive T cells can mediate detrimental graft-versushost disease (GVHD) as well as beneficial graft-versustumor (GVT) responses after allogeneic stem cell transplantation
In later studies it was shown that HA-1–specific immune responses dominated in patients that experienced beneficial GVT responses [5], and that the expression profile of HA-1 was in accordance with a relative specific antileukemia reactivity of the T cells, because HA-1 is exclusively expressed by the hematopoietic lineage [6]
The presence of allo-human leukocyte antigen (HLA)–restricted tumor-associated antigens (TAA)-specific T cells was analyzed in a patient transplanted with a single HLAA2–mismatched stem cell transplantation (SCT) that experienced GVHD after treatment with donor lymphocyte infusion (DLI) for relapsed acute myeloid leukemia (AML)
Summary
Alloreactive T cells can mediate detrimental graft-versushost disease (GVHD) as well as beneficial graft-versustumor (GVT) responses after allogeneic stem cell transplantation (allo-SCT). Analysis of the clinical responses of allo-SCT patients and the TCR repertoire of the alloreactive immune responses showed that beneficial GVT responses more frequently occur when the severity of the GVHD response increases due to the activation of polyclonal responses [3] This phenomenon is illustrated by the work of Goulmy and colleagues showing that a mismatch for the polymorphic peptide HA-1 was associated with a high risk of severe GVHD, indicating in first instance that HA-1–specific T cells may induce GVHD responses [4]. In later studies it was shown that HA-1–specific immune responses dominated in patients that experienced beneficial GVT responses [5], and that the expression profile of HA-1 was in accordance with a relative specific antileukemia reactivity of the T cells, because HA-1 is exclusively expressed by the hematopoietic lineage [6] These results imply that despite an overall detrimental clinical phenotype, beneficial GVT reactivities can appear www.aacrjournals.org
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