Antisera induced by infusions of autologous Ad-CD154-leukemia B cells identify ROR1 as an oncofetal antigen and receptor for Wnt5a.
We examined the sera of six patients before and after i.v. infusions of autologous chronic lymphocytic leukemia (CLL) cells transduced ex vivo with an adenovirus encoding CD154 (Ad-CD154). Five patients made high-titer antibodies against adenovirus and three made IgG reactive with a leukemia-associated surface antigen, which we identified as ROR1. Anti-ROR1 antibodies were not detected in the sera of untreated patients. We generated anti-ROR1 mAbs and found they reacted specifically with the CLL cells of all patients, but not with nonleukemic leukocytes, a wide variety of normal adult tissues, or blood mononuclear cells, including CD5(+) B cells of healthy adults. ROR1 could bind Wnt5a, which induced activation of NF-kappaB when coexpressed with ROR1 in HEK293 cells and enhanced the survival of CLL cells in vitro, an effect that could be neutralized by posttreatment anti-ROR1 antisera. We conclude that patients with CLL can break immune tolerance to ROR1, which is an oncofetal surface antigen and survival-signaling receptor in this neoplastic disease.
Fukuda
Tetsuya
T
Moores Cancer Center, and Chronic Lymphocytic Leukemia Research Consortium, University of California at San Diego, La Jolla, CA 92093, USA.
Chen
Liguang
L
Endo
Tomoyuki
T
Tang
Li
L
Lu
Desheng
D
Castro
Januario E
JE
Widhopf
George F
GF
Rassenti
Laura Z
LZ
Cantwell
Mark J
MJ
Prussak
Charles E
CE
Carson
Dennis A
DA
Kipps
Thomas J
TJ
D000256:Adenoviridae / Q000276:immunology; D000818:Animals; D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm / Q000276:immunology / Q000378:metabolism; D001483:Base Sequence; D023201:CD40 Ligand / Q000276:immunology*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D017931:DNA Primers; D018076:DNA, Complementary / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D007106:Immune Sera / Q000276:immunology*; D015151:Immunoblotting; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology*; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D057050:Receptor Tyrosine Kinase-like Orphan Receptors; D017422:Sequence Analysis, DNA; D014407:Tumor Cells, Cultured; D051153:Wnt Proteins / Q000378:metabolism*; D000071818:Wnt-5a Protein
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D017931:DNA Primers; D018076:DNA, Complementary; D007106:Immune Sera; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C031192:oncofetal antigens; D023201:CD40 Ligand; C078716:ROR1 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D057050:Receptor Tyrosine Kinase-like Orphan Receptors