Leukemia-specific T-cell reactivity induced by leukemic dendritic cells is augmented by 4-1BB targeting.
OBJECTIVE
Acute myelogenous leukemia (AML) blasts are able to differentiate into leukemia-derived dendritic cells (AML-DC), thereby enabling efficient presentation of known and unknown leukemic antigens. Advances in culture techniques and AML-DC characterization justify clinical application. However, additional measures are likely needed to potentiate vaccines and overcome the intrinsic tolerant state of the patients' immune system. Engagement of the costimulatory molecule 4-1BB can break immunologic tolerance and increase CTL responses. In this study, we examined the role of the 4-1BB ligand (4-1BBL) on T-cell responses induced by AML-DC.


METHODS
In allogeneic and autologous cocultures of T cells and AML-DC, the effect of the addition of 4-1BBL on T-cell proliferation, T-cell subpopulations, and T-cell function was determined.


RESULTS
Addition of 4-1BBL to cocultures of AML-DC and T cells induced a preferential increase in the proliferation of CD8(+) T cells. Increased differentiation into effector and central memory populations was observed in both CD4(+) and CD8(+) T cells in the presence of 4-1BBL. AML-DC induce a T helper 1 response, characterized by high IFN-gamma production, which is significantly increased by targeting 4-1BB. T cells primed in the presence of 4-1BBL show specificity for the leukemia-associated antigen Wilms' tumor 1, whereas cytotoxicity assays with leukemic blast targets showed the cytolytic potential of T cells primed in the presence of 4-1BBL.


CONCLUSIONS
We conclude that 4-1BBL is an effective adjuvant to enhance T-cell responses elicited by AML-DC.
Houtenbos
Ilse
I
Department of Hematology, VU University Medical Center, Amsterdam, the Netherlands.
Westers
Theresia M
TM
Dijkhuis
Annemiek
A
de Gruijl
Tanja D
TD
Ossenkoppele
Gert J
GJ
van de Loosdrecht
Arjan A
AA
D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D016130:Immunophenotyping; D020014:K562 Cells; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism*; D008024:Ligands; D008213:Lymphocyte Activation; D013601:T-Lymphocytes / Q000378:metabolism*; D013997:Time Factors; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000378:metabolism*
D016207:Cytokines; D008024:Ligands; C505714:TNFRSF9 protein, human; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9