title: Cross-protective murine graft-versus-leukemia responses to phenotypically distinct myeloid leukemia lines.
abstract: A c-myc retrovirus-transformed myeloid leukemia line, MMB3.19, of C57BL/6 (B6) origin, was developed to investigate graft-versus-leukemia (GVL) activity in murine bone marrow transplantation (BMT) models. It was previously determined that both naive and leukemia-presensitized CD4+-enriched T cells are capable of mediating GVL activity to MMB3.19 challenge in both syngeneic (B6) and allogeneic (C3H.SW-->B6) strain combinations, with the latter coinciding with minimal graft-versus-host disease. In the present study, MMB3.19 and 2 other similarly derived, yet phenotypically diverse, B6 myeloid leukemia lines (MMB1.10 and MMB2.18) were investigated for potential shared tumor antigens in the syngeneic GVL model. Morphologically, all 3 tumor lines are blastic with high cytoplasmic:nuclear ratios, but MMB2.18 displays dendritic processes, whereas MMB1.10 and MMB3.19 have a more rounded appearance. Flow cytometric analysis of the 3 lines revealed constitutive surface molecule expression of Mac-1, Mac-2, F4/80, LFA-1, B7-1, B7-2, H2Kb, H2Db, and macrophage scavenger receptor, consistent with macrophage/monocyte lineages. Furthermore, each of the lines expresses H2I-Ab, but to varying degrees, with MMB2.18 cells having the lowest percentage (31.6%). In vitro 51Cr release assays using MMB3.19-primed T-cell effectors demonstrated equivalent specific lysis of all 3 leukemia-line target cells. In addition, enzyme-linked immunospot analysis of MMB3.19-primed CD4+ T cells revealed significantly increased frequencies of tumor-stimulated interleukin (IL)-2-, IL-4-, and interferon-gamma-secreting cells when restimulated with each of the 3 leukemia lines. Furthermore, when MMB3.19-primed CD4+ T cells were administered in a BMT setting, a protective GVL effect was seen in those mice challenged with MMB1.10, MMB2.18, or MMB3.19. Therefore, in vitro and in vivo experiments indicate that the 3 distinct myeloid leukemia lines share 1 or more common major histocompatibility complex class II-restricted tumor antigens that can elicit a cross-protective in vivo T-cell GVL response.
authors.affiliation: Kimmel Cancer Institute, Jefferson Medical College, Philadelphia, Pennsylvania 19107, USA.
authors.forename: A E
authors.initials: AE
authors.lastname: Patterson
authors.forename: R
authors.initials: R
authors.lastname: Korngold
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000032:analysis / Q000276:immunology*; D000954:Antigens, Surface / Q000032:analysis; D016026:Bone Marrow Transplantation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D002461:Cell Line, Transformed; D019070:Cell Lineage; D002467:Cell Nucleus / Q000648:ultrastructure; D003593:Cytoplasm / Q000648:ultrastructure; D003712:Dendrites / Q000648:ultrastructure; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D016259:Genes, myc; D020544:Graft vs Leukemia Effect / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000032:analysis; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D007951:Leukemia, Myeloid / Q000276:immunology / Q000473:pathology*; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D011828:Radiation Chimera; D014184:Transplantation, Homologous; D014407:Tumor Cells, Cultured / Q000276:immunology / Q000378:metabolism / Q000648:ultrastructure
chemical_list: D000951:Antigens, Neoplasm; D000954:Antigens, Surface; D000949:Histocompatibility Antigens Class II; D007376:Interleukin-2; D015847:Interleukin-4; D007371:Interferon-gamma