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Leukemia-Specific T-Cell Reactivity Induced by Leukemic Dendritic Cells Is Augmented by 4-1BB Targeting

Authors' Affiliations: Departments of ¹ Hematology and ² Medical Oncology, VU University Medical Center, Amsterdam, the Netherlands

Requests for reprints: Arjan A. van de Loosdrecht, Department of Hematology, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, the Netherlands. Phone: 31-20-4442604; Fax: 31-20-4442601; E-mail: a.vandeloosdrecht{at}vumc.nl.

Purpose: 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.

Experimental Design: 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- 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.

Conclusion: We conclude that 4-1BBL is an effective adjuvant to enhance T-cell responses elicited by AML-DC.

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