The Hematopoietic System–specific Minor Histocompatibility Antigen HA-1 Shows Aberrant Expression in Epithelial Cancer Cells

Abstract

Allogeneic stem cell transplantation (SCT) can induce curative graft-versus-tumor reactions in patients with hematological malignancies and solid tumors. The graft-versus-tumor reaction after human histocompatibility leukocyte antigen (HLA)-identical SCT is mediated by alloimmune donor T cells specific for polymorphic minor histocompatibility antigens (mHags). Among these, the mHag HA-1 was found to be restricted to the hematopoietic system. Here, we report on the HA-1 ribonucleic acid expression by microdissected carcinoma tissues and by single disseminated tumor cells isolated from patients with various epithelial tumors. The HA-1 peptide is molecularly defined, as it forms an immunogenic peptide ligand with HLA-A2 on the cell membrane of carcinoma cell lines. HA-1–specific cytotoxic T cells lyse epithelial tumor cell lines in vitro, whereas normal epithelial cells are not recognized. Thus, HA-1–specific immunotherapy combined with HLA-identical allogeneic SCT may now be feasible for patients with HA-1+ carcinomas.

Aberrant expression of the hematopoietic-restricted minor histocompatibility antigen LRH-1 on solid tumors results in efficient cytotoxic T cell-mediated lysis

“…Here, we analyzed the expression of the LRH-1-encoding P2X5 gene in a large panel of solid tumor cell lines and primary tumor specimens using real-time quantitative RT-PCR. SigniWcant P2X5 mRNA levels were detected in 31% of the solid tumor cell lines tested, including RCC, melanoma, colorectal carcinoma, [12,16], ECGF-1 [23], and BCL2A1 [2,24]. Enlargement of the panel of MiHA is essential for development of eVective post-transplantation immunotherapy.…”

“…Therefore, it would be highly beneWcial to direct donor T cell immunity towards MiHA that are selectively co-expressed on hematopoietic cells and solid tumor cells by vaccination or T cell therapy. Only a few hematopoietic-restricted MiHA have been described that are aberrantly expressed on solid tumors, including HA-1 [12,16], ECGF-1 [23] and BCL2A1 [2,24]. Therefore, it is important to enlarge the panel of MiHA that can be used for immunotherapy of solid tumors.…”

Genetic polymorphisms predicting the outcome of bone marrow transplants

“…The subsequent emergence of HA-1-and HA-2-specific CD8 + T cells in the peripheral blood of the recipients led to complete remission of the leukaemia and 100% donor chimaerism (Marijt et al, 2003). mHag HA-1 is also expressed on epithelial cancer cells and not on normal epithelial cells, giving rise to the concept of the use of mHag in more diverse cancer therapies (Klein et al, 2002).…”

Steric Hindrance and Fast Dissociation Explain the Lack of Immunogenicity of the Minor Histocompatibility HA-1Arg Null Allele

“…inor histocompatibility Ags play important roles in the outcome of stem cell transplantation (SCT) 5 and organ transplantation. In HLA-identical SCT minor histocompatibility Ags are involved in the development of graft-versushost disease and in the graft-versus-tumor reactivity (1).…”