C19orf48 encodes a minor histocompatibility antigen recognized by CD8+ cytotoxic T cells from renal cell carcinoma patients

Tykodi, Scott S. [Fred Hutchinson Cancer Research Center & University of Washington, Seattle, Washington (USA)] Fujii, Nobuharu [Fred Hutchinson Cancer Research Center & University of Washington, Seattle, Washington (USA)] Vigneron, Nathalie [Yale University School of Medicine, New Haven, CT (USA) & UCL] Lu, Sharon M. [Yale University School of Medicine, New Haven, CT (USA)] Mito, Jeffrey K. [Fred Hutchinson Cancer Research Center] Miranda, Maureen X. [Fred Hutchinson Cancer Research Center] Chou, Jeffrey [Fred Hutchinson Cancer Research Center & University of Washington, Seattle, Washington (USA)] Voong, Lilien N. [Fred Hutchinson Cancer Research Center] Thompson, John A. [Fred Hutchinson Cancer Research Center & University of Washington, Seattle, Washington (USA)] Sandmaier, Brenda M. [Fred Hutchinson Cancer Research Center & University of Washington, Seattle, Washington (USA)] Cresswell, Peter [Yale University School of Medicine, New Haven, CT (USA)] Van den Eynde, Benoît [UCL] Riddell, Stanely R. [Fred Hutchinson Cancer Research Center & University of Washington, Seattle, Washington (USA)] Warren, Edus H. [Fred Hutchinson Cancer Research Center & University of Washington, Seattle, Washington (USA)] et al.[show all]

PURPOSE: Tumor regression has been observed in some patients with metastatic renal cell carcinoma (RCC) after nonmyeloablative allogeneic hematopoietic cell transplantation (HCT). Cellular and molecular characterization of antigens recognized by tumor-reactive T cells isolated from responding patients could potentially provide insight into the mechanisms of tumor regression. EXPERIMENTAL DESIGN: CD8+ CTL clones that recognized a novel RCC-associated minor histocompatibility (H) antigen presented by HLA-A*0201 were isolated from two patients with metastatic RCC who experienced tumor regression or stable disease following nonmyeloablative allogeneic HCT. These clones were used to screen a cDNA library and isolate the unique cDNA encoding the antigen. RESULTS: An alternative open reading frame in the C19orf48 gene located on chromosome 19q13 encodes the HLA-A*0201-restricted minor H antigen recognized by the RCC-reactive T cells. The differential T-cell recognition of donor- and recipient-derived target cells is attributable to a nonsynonymous single-nucleotide polymorphism within the nucleotide interval that encodes the antigenic peptide. Assays for gene expression and CTL recognition showed that the C19orf48-encoded peptide is widely expressed in renal tumors and solid tumors of other histologies. The antigenic peptide can be processed for CTL recognition via both TAP-dependent and TAP-independent pathways. CONCLUSIONS: Donor T-cell responses against the HLA-A*0201-restricted minor H antigen encoded by C19orf48 may contribute to RCC regression after MHC-matched allogeneic HCT.