Targeting minor histocompatibility antigens in graft versus tumor or graft versus leukemia responses

Abstract

Allogeneic hematopoietic cell transplantation (alloHCT) represents the only curative therapy for several hematologic malignancies, and shows promise as a nascent treatment modality for select solid tumors. Although the original goal of alloHCT was hematopoietic reconstitution after sub-lethal chemoradiotherapy, recognition of a profound donor lymphocyte-mediated graft-versus-leukemia (GVL) or graft-versus-tumor (GVT) effect has shifted the paradigm from pre-transplant cytoreduction to tumor control via donor lymphocytes. In human leukocyte antigen (HLA)-compatible alloHCT, GVL and GVT reactions are induced primarily by donor T-cell recognition of minor histocompatibility antigens (mHAgs). Here we review the literature regarding mHAg-specific T cells in GVL and GVT reactions, and discuss the prospects of exploiting mHAgs as immunotherapeutic targets.

Figure 1

Induction of graft-versus host reactivity, including GVL and GVT effects. In order for donor-anti-recipient T-cell (CD4⁺ or CD8⁺) effector activity to occur during alloHCT in response to a given mHAg, recipient cells must express the polymorphic allele which encodes the mHAg peptide, whereas donor cells (indicated in blue) must not express the allele that encodes the mHAg. Thus, to elicit GVL or GVT reactivity, the recipient must be genetically homozygous or heterozygous for the mHAg-encoding allele (i.e. mHAg-positive), and the donor must be homozygous for the alternate polymorphic allele (or lack it altogether), which does not encode the mHAg. Frequently, the mHAg allelic disparity between donor and recipient is the result of a single nucleotide polymorphism, which can in turn result in the substitution of a single amino acid residue in an MHC-bound peptide, as represented by a single red circle within a blue peptide epitope. Upon recognition by the donor T-cell receptor of a genetically disparate ‘non-self’ mHAg peptide-MHC complex, the donor CTL can eradicate the mHAg-positive recipient cell via cytolytic activity. Donor-derived normal hematopoietic cells which reconstitute the graft after alloHCT are spared from donor T-cell mediated cytotoxicity because they are immunogenetically ‘self’ and do not express mHAg epitopes.