Leukemia-associated antigenic isoforms induce a specific immune response in children with T-ALL.

The potential immunogenicity of acute lymphoblastic leukemia of the T cell (T-ALL), a small subgroup of childhood leukemia with increased risk for treatment failure and early relapse, was addressed by serological identification of leukemia-derived antigens by recombinant expression cloning (SEREX). Thirteen antigens with homology to known genes that are involved in critical cellular processes were detected. Further characterization of the 4 novel isoforms revealed that 3 (HECTD1Delta, CX-ORF-15Delta and hCAP-EDelta) had restricted mRNA expression in more than 70% of T-ALLs (n = 22) and that specific antibodies against these isoforms were detected in up to 30% of patients (n = 16), with the highest frequency for HECTD1Delta. The latter protein was present at high abundance in T-ALLs but not in normal hematopoietic tissues. Given that the leukemia-associated antigens detected in this study have an intracellular localization, the generation of immune effector responses most likely requires antigen presentation. To test this assumption, dendritic cells were loaded with HECTD1Delta protein and used for T cell stimulation. A specific T cell response was induced in vitro in all 3 healthy donors studied, including a former T-ALL patient. These data suggest that T-ALL may induce a specific cellular and humoral antileukemia immune response in children, thereby supporting new approaches for immunotherapy.