title: Minor antigen distribution predicts site-specific graft-versus-tumor activity of adoptively transferred, minor antigen-specific CD8 T Cells.
abstract: The clinical success of allogeneic T cell therapy for cancer relies on the selection of antigens that can effectively elicit antitumor responses with minimal toxicity toward nonmalignant tissues. Although minor histocompatibility antigens (MiHA) represent promising targets, broad expression of these antigens has been associated with poor responses and T cell dysfunction that may not be prevented by targeting MiHA with limited expression. In this study, we hypothesized that antitumor activity of MiHA-specific CD8 T cells after allogeneic bone marrow transplantation (BMT) is determined by the distribution of antigen relative to the site of tumor growth. To test this hypothesis, we utilized the clinically relevant male-specific antigen HY and studied the fate of adoptively transferred, HY-CD8(+) T cells (HY-CD8) against a HY-expressing epithelial tumor (MB49) and pre-B cell leukemia (HY-E2APBX ALL) in BMT recipients. Transplants were designed to produce broad HY expression in nonhematopoietic tissues (female → male BMT, [F → M]), restricted HY expression in hematopoietic tissues (male → female BMT, [M → F]) tissues, and no HY tissue expression (female → female BMT, [F → F]). Broad HY expression induced poor responses to MB49 despite sublethal graft-versus-host disease and accumulation of HY-CD8 in secondary lymphoid tissues. Antileukemia responses, however, were preserved. In contrast, restriction of HY expression to hematopoietic tissues restored MB49 responses but resulted in a loss of antileukemia responses. We concluded that target alloantigen expression in the same compartment of tumor growth impairs CD8 responses to both solid and hematologic tumors.
authors.affiliation: Blood and Marrow Transplant Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. Electronic address: Jessica_Shand@URMC.Rochester.edu.
authors.forename: Jessica C
authors.initials: JC
authors.lastname: Shand
authors.affiliation: Blood and Marrow Transplant Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Haiying
authors.initials: H
authors.lastname: Qin
authors.affiliation: Blood and Marrow Transplant Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Nicole
authors.initials: N
authors.lastname: Nasholm
authors.affiliation: Department of Pediatrics and UW Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Christian M
authors.initials: CM
authors.lastname: Capitini
authors.affiliation: Blood and Marrow Transplant Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Terry J
authors.initials: TJ
authors.lastname: Fry
mesh_terms: D019264:Adoptive Transfer; D000483:Alleles; D000818:Animals; D016026:Bone Marrow Transplantation; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000637:transplantation; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology; D005260:Female; D015870:Gene Expression / Q000276:immunology; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D020544:Graft vs Leukemia Effect; D006182:H-Y Antigen / Q000235:genetics / Q000276:immunology*; D006801:Humans; D016130:Immunophenotyping; D008212:Lymphocyte Depletion; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000276:immunology* / Q000401:mortality / Q000628:therapy; D054448:Precursor Cells, B-Lymphoid / Q000276:immunology / Q000473:pathology; D016019:Survival Analysis
chemical_list: D006182:H-Y Antigen
keywords: Acute lymphoblastic leukemia; Adoptive T cell therapy; Allogeneic transplantation; CD8 T cell function; Minor histocompatibility antigens