Apoptotic blebs from leukemic cells as a preferred source of tumor-associated antigen for dendritic cell-based vaccines
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Since few leukemia-associated antigens (LAA) are characterized for acute myeloid leukemia (AML), apoptotic tumor cells constitute an attractive LAA source for DC-based vaccines, as they contain both characterized and unknown LAA. However, loading DC with apoptotic tumor cells may interfere with DC function. Previously, it was shown in mice that apoptotic blebs induce DC maturation, whereas apoptotic cell remnants (ACR) do not. Here, we analyzed human monocyte-derived DC (MoDC) functionality in vitro, after ingesting either allogeneic AML-derived ACR or blebs. We show that MoDC ingest blebs to a higher extent and are superior in migrating toward CCL19, as compared to ACR-loaded MoDC. Although MoDC cytokine production was unaffected, co-culturing bleb-loaded MoDC with T cells led to an increased T cell proliferation and IFNγ production. Moreover, antigen-specific CD8+ T cells frequencies increased to 0.63 % by priming with bleb-loaded MoDC, compared to 0.16 % when primed with ACR-loaded MoDC. Importantly, CD8+ T cells primed by bleb-loaded MoDC recognized their specific epitope at one to two orders of magnitude lower concentrations compared to ACR-loaded MoDC. In conclusion, superior ingestion efficiency and migration, combined with favorable T cell cytokine release and CD8+ T cell priming ability and avidity, point to blebs as the preferred component of apoptotic leukemic cells for LAA loading of DC for the immunotherapy of AML.
KeywordsDendritic cell vaccination Dendritic cell loading Apoptotic tumor cells Blebs T cell priming Anti-tumor immunity
We would like to thank Professor Dr. Rob Beelen and Donna Fluitsma from the department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, the Netherlands, for facilitating the electron microscopic analysis and their technical assistance therein. Furthermore, we would like to thank Dr. Teun de Vries, Ton Schoenmaker, and Cor Semeins from the department of Periodontology and Oral Cell Biology, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and VU University Amsterdam, Amsterdam, the Netherlands, for facilitating the confocal microscope and providing technical assistance.
Conflict of interest
The authors have no conflicts of interest to disclose.
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