title: A polymorphism in the splice donor site of ZNF419 results in the novel renal cell carcinoma-associated minor histocompatibility antigen ZAPHIR.
abstract: Nonmyeloablative allogeneic stem cell transplantation (SCT) can induce remission in patients with renal cell carcinoma (RCC), but this graft-versus-tumor (GVT) effect is often accompanied by graft-versus-host disease (GVHD). Here, we evaluated minor histocompatibility antigen (MiHA)-specific T cell responses in two patients with metastatic RCC who were treated with reduced-intensity conditioning SCT followed by donor lymphocyte infusion (DLI). One patient had stable disease and emergence of SMCY.A2-specific CD8+ T cells was observed after DLI with the potential of targeting SMCY-expressing RCC tumor cells. The second patient experienced partial regression of lung metastases from whom we isolated a MiHA-specific CTL clone with the capability of targeting RCC cell lines. Whole genome association scanning revealed that this CTL recognizes a novel HLA-B7-restricted MiHA, designated ZAPHIR, resulting from a polymorphism in the splice donor site of the ZNF419 gene. Tetramer analysis showed that emergence of ZAPHIR-specific CD8+ T cells in peripheral blood occurred in the absence of GVHD. Furthermore, the expression of ZAPHIR in solid tumor cell lines indicates the involvement of ZAPHIR-specific CD8+ T cell responses in selective GVT immunity. These findings illustrate that the ZNF419-encoded MiHA ZAPHIR is an attractive target for specific immunotherapy after allogeneic SCT.
authors: Department of Laboratory Medicine-Laboratory of Hematology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors: Kelly
authors: K
authors: Broen
authors: Henriette
authors: H
authors: Levenga
authors: Johanna
authors: J
authors: Vos
authors: Kees
authors: K
authors: van Bergen
authors: Hanny
authors: H
authors: Fredrix
authors: Annelies
authors: A
authors: Greupink-Draaisma
authors: Michel
authors: M
authors: Kester
authors: J H Frederik
authors: JH
authors: Falkenburg
authors: Pieter
authors: P
authors: de Mulder
authors: Theo
authors: T
authors: de Witte
authors: Marieke
authors: M
authors: Griffioen
authors: Harry
authors: H
authors: Dolstra
mesh_terms: D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000628:therapy; D002478:Cells, Cultured; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D015778:Minor Histocompatibility Antigens / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics*; D022821:RNA Splice Sites / Q000235:genetics*; D033581:Stem Cell Transplantation; D014184:Transplantation, Homologous
chemical_list: D015778:Minor Histocompatibility Antigens; D022821:RNA Splice Sites