title: Serologic markers of effective tumor immunity against chronic lymphocytic leukemia include nonmutated B-cell antigens.
abstract: Patients with chronic lymphocytic leukemia (CLL) who relapse after allogeneic transplant may achieve durable remission following donor lymphocyte infusion (DLI), showing the potency of donor-derived immunity in eradicating tumors. We sought to elucidate the antigenic basis of the effective graft-versus-leukemia (GvL) responses associated with DLI for the treatment of CLL by analyzing the specificity of plasma antibody responses developing in two DLI-treated patients who achieved long-term remission without graft-versus-host disease. By probing high-density protein microarrays with patient plasma, we discovered 35 predominantly intracellular antigens that elicited high-titer antibody reactivity greater in post-DLI than in pre-DLI plasma. Three antigens-C6orf130, MDS032, and ZFYVE19-were identified by both patients. Along with additional candidate antigens DAPK3, SERBP1, and OGFOD1, these proteins showed higher transcript and protein expression in B cells and CLL cells compared with normal peripheral blood mononuclear cells. DAPK3 and the shared antigens do not represent minor histocompatibility antigens, as their sequences are identical in both donor and tumor. Although ZFYVE19, DAPK3, and OGFOD1 elicited minimal antibody reactivity in 12 normal subjects and 12 chemotherapy-treated CLL patients, 5 of 12 CLL patients with clinical GvL responses were serologically reactive to these antigens. Moreover, antibody reactivity against these antigens was temporally correlated with clinical disease regression. These B-cell antigens represent promising biomarkers of effective anti-CLL immunity.
authors.affiliation: Cancer Vaccine Center and Departments of Medical Oncology and Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors.forename: Ovidiu
authors.initials: O
authors.lastname: Marina
authors.forename: Ursula
authors.initials: U
authors.lastname: Hainz
authors.forename: Melinda A
authors.initials: MA
authors.lastname: Biernacki
authors.forename: Wandi
authors.initials: W
authors.lastname: Zhang
authors.forename: Ann
authors.initials: A
authors.lastname: Cai
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Duke-Cohan
authors.forename: Fenglong
authors.initials: F
authors.lastname: Liu
authors.forename: Vladimir
authors.initials: V
authors.lastname: Brusic
authors.forename: Donna
authors.initials: D
authors.lastname: Neuberg
authors.forename: Jeffery L
authors.initials: JL
authors.lastname: Kutok
authors.forename: Edwin P
authors.initials: EP
authors.lastname: Alyea
authors.forename: Christine M
authors.initials: CM
authors.lastname: Canning
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Soiffer
authors.forename: Jerome
authors.initials: J
authors.lastname: Ritz
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Wu
mesh_terms: D000954:Antigens, Surface / Q000032:analysis* / Q000097:blood / Q000235:genetics / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D014408:Biomarkers, Tumor / Q000032:analysis / Q000097:blood* / Q000235:genetics; D016026:Bone Marrow Transplantation / Q000276:immunology; D019070:Cell Lineage / Q000276:immunology; D005260:Female; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology*; D016056:Immunodominant Epitopes / Q000032:analysis / Q000097:blood; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood / Q000175:diagnosis / Q000276:immunology* / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000502:physiology; D011379:Prognosis; D040081:Protein Array Analysis; D016896:Treatment Outcome
chemical_list: D000954:Antigens, Surface; D014408:Biomarkers, Tumor; D016056:Immunodominant Epitopes