Minor Antigen Distribution Predicts Site-Specific Graft-versus-Tumor Activity of Adoptively Transferred, Minor Antigen-Specific CD8 T Cells

• Published in: Biology of blood and marrow transplantation Vol. 20; no. 1; pp. 26 - 36
• Main Authors: Shand, Jessica C, Qin, Haiying, Nasholm, Nicole, Capitini, Christian M, Fry, Terry J
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2014
• Subjects: Acute lymphoblastic leukemia; Adoptive T cell therapy; Adoptive Transfer; Alleles; Allogeneic transplantation; Animals; Bone Marrow Transplantation; CD8-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - transplantation; CD8 T cell function; Cell Proliferation; Dendritic Cells - immunology; Dendritic Cells - pathology; Female; Gene Expression - immunology; Graft vs Host Disease - genetics; Graft vs Host Disease - immunology; Graft vs Host Disease - mortality; Graft vs Host Disease - pathology; Graft vs Leukemia Effect; H-Y Antigen - genetics; H-Y Antigen - immunology; Hematology, Oncology and Palliative Medicine; Humans; Immunophenotyping; Lymphocyte Depletion; Male; Mice; Mice, Transgenic; Minor histocompatibility antigens; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - immunology; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - mortality; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - therapy; Precursor Cells, B-Lymphoid - immunology; Precursor Cells, B-Lymphoid - pathology; Survival Analysis; CD8 T cell function; Acute lymphoblastic leukemia; Allogeneic transplantation; Minor histocompatibility antigens; Adoptive T cell therapy
• ISSN: 1083-8791; 1523-6536
• DOI: 10.1016/j.bbmt.2013.10.009

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.