High avidity myeloid leukemia-associated antigen-specific CD8+ T cells preferentially reside in the bone marrow

Abstract

The activity of allogeneic CD8 ؉ T cells specific for leukemia-associated antigens (LAAs) is thought to mediate, at least in part, the curative effects of hematopoietic stem cell transplantation (HSCT) in myeloid malignancies. However, the identity and nature of clinically relevant LAA-specific CD8 ؉ T-cell populations have proven difficult to define. Here, we used a combination of coreceptormutated peptide-major histocompatibility complex class I (pMHCI) tetramers and polychromatic flow cytometry to examine the avidity profiles, phenotypic characteristics, and anatomical distribution of HLA A*0201-restricted CD8 ؉ T-cell populations specific for LAAs that are over-expressed in myeloid leukemias. Remarkably, LAA-specific CD8 ؉ T-cell populations, regardless of fine specificity, were confined almost exclusively to the bone marrow; in contrast, CD8 ؉ T-cell populations specific for the HLA A*0201-restricted cytomegalovirus (CMV) pp65 495-503 epitope were phenotypically distinct and evenly distributed between bone marrow and peripheral blood. Furthermore, bone marrow-resident LAA-specific CD8 ؉ T cells frequently engaged cognate antigen with high avidity; notably, this was the case in all tested bone marrow samples derived from patients who achieved clinical remission after HSCT. These data suggest that concomitant examination of bone marrow specimens in patients with myeloid leukemias might yield more definitive information in the search for immunologic prognostica- IntroductionAllogeneic hematopoietic stem cell transplantation (HSCT) can be curative in a large proportion of patients with myeloid malignancies and there is substantial evidence to support the notion that this is mediated, at least to some extent, by a graft-versus-leukemia (GVL) effect. 1 However, the precise identity of the allogeneic leukemia-reactive T cells that are responsible for the GVL effect remains obscure. It is established that certain proteins are overexpressed in leukemic states. Peptides derived from these proteins can be displayed at high densities bound to major histocompatibility complex class I (MHCI) molecules on the cell surface and act as leukemia-associated antigens (LAAs) for immune recognition. 2 Two such well-studied LAAs that are known to elicit human leukocyte antigen (HLA) A*0201-restricted CD8 ϩ T-cell responses are the PR3 169-177 /HNE 168-176 (PR1) and WT1 126-134 epitopes derived from proteinase 3/human neutrophil elastase and Wilms tumor antigen-1, respectively. [3][4][5][6][7][8] The selective recognition and elimination of leukemic but not healthy hematopoietic progenitor cells by CD8 ϩ T cells specific for indicates that these LAAs might be useful target antigens for immunotherapeutic interventions. However, it remains unclear to what extent such LAA-specific CD8 ϩ T-cell responses mediate protective effects in vivo before and after HSCT. 9 In part, this reflects limitations of current technological approaches to the detection of low frequency antigen-specific CD8 ϩ T cells directly ex vivo; furthermore, for re...

Induction of multiple myeloma-reactive T cells during post-transplantation immunotherapy with donor lymphocytes and recipient DCs

“…Previously, it has been described that high-avidity leukemia-reactive T cells reside preferentially in the BM in contrast to other specific T-cell populations that are evenly distributed between BM and peripheral blood. 18 Although we, at this stage, have no information or possibilities to explore the avidity of CTL clone 44, we showed that this population does reside almost exclusively in the BM confirming previous studies. CD8 þ T cells homing to the BM have a specific chemokine receptor profile, distinct from T cells homing to secondary lymphoid organs.…”

Leukemia-associated antigens and their relevance to the immunotherapy of acute myeloid leukemia

“…Several authors have observed decreased relapse rates among transplant patients with myeloid malignancies who develop CTL immunity to PR1. 61,97 Kapp et al 61 were able to extend these findings to other LAAs by demonstrating that the risk of post-transplant AML relapse depended on the presence or absence of CTL immunity to PR1, WT1 and/or MUC1. 61 Similarly, Molldrem et al 78 observed a trend toward a lower relapse rate in allo-transplanted AML patients exhibiting CTL activity to myeloperoxidase.…”

“…The emergence of LAA-specific immune responses after allogeneic HSCT or DLI has been shown to coincide with the induction of clinical responses, suggesting a prominent role of LAAs in mediating GvL. 97 With the exception of one report that questioned the proper functionality of LAAspecific T cells present after allogeneic HSCT, 62 studies have consistently documented the positive impact of LAA-specific immunity on post-transplant clinical outcomes. Several authors have observed decreased relapse rates among transplant patients with myeloid malignancies who develop CTL immunity to PR1.…”

Expansion of highly differentiated CD8+ T-cells or NK-cells in patients treated with dasatinib is associated with cytomegalovirus reactivation

“…Notably, we also detected CD8 þ T-cells specific for the leukemia-associated antigen PR1 in 3 LGL patients, 2 of them with complete remission status despite initially poor prognoses. Such CD8 þ T-cell populations are difficult to detect in peripheral blood; 48 it is therefore possible that larger numbers of these cells might reside in the bone marrow of patients with dasatinib-associated LGL, contributing to the link between elevated levels of cytokines/chemokines and favorable outcome.…”