Induction of antitumor cytotoxic lymphocytes using engineered human primary blood dendritic cells
JournalProceedings of the National Academy of Sciences of the United States of America
PublisherNational Academy of Sciences
MetadataShow full item record
AbstractDendritic cell (DC)-based cancer immunotherapy has achieved modest clinical benefits, but several technical hurdles in DC preparation, activation, and cancer/testis antigen (CTA) delivery limit its broad applications. Here, we report the development of immortalized and constitutively activated human primary blood dendritic cell lines (ihv-DCs). The ihv-DCs are a subset of CD11c+/CD205+ DCs that constitutively display costimulatory molecules. The ihv-DCs can be genetically modified to express human telomerase reverse transcriptase (hTERT) or the testis antigen MAGEA3 in generating CTA-specific cytotoxic T lymphocytes (CTLs). In an autologous setting, the HLA-A2+ ihv-DCs that present hTERT antigen prime autologous T cells to generate hTERT-specific CTLs, inducing cytolysis of hTERT-expressing target cells in an HLA-A2–restricted manner. Remarkably, ihv-DCs that carry two allogeneic HLA-DRB1 alleles are able to prime autologous T cells to proliferate robustly in generating HLA-A2–restricted, hTERT-specific CTLs. The ihv-DCs, which are engineered to express MAGEA3 and high levels of 4-1BBL and MICA, induce simultaneous production of both HLA-A2–restricted, MAGEA3-specific CTLs and NK cells from HLA-A2+ donor peripheral blood mononuclear cells. These cytotoxic lymphocytes suppress lung metastasis of A549/A2.1 lung cancer cells in NSG mice. Both CTLs and NK cells are found to infiltrate lung as well as lymphoid tissues, mimicking the in vivo trafficking patterns of cytotoxic lymphocytes. This approach should facilitate the development of cell-based immunotherapy for human lung cancer. Copyright 2018 National Academy of Sciences. All rights reserved.
SponsorsACKNOWLEDGMENTS. We thank Alonso Heredia, Yiling Liu, and Suzanne Gartner for technical assistance. Research reported in this publication was supported by the University of Maryland Cancer Center and the Institute of Human Virology, University of Maryland School of Medicine (H.C.).
Cytotoxic T lymphocytes
Human blood dendritic cells
Identifier to cite or link to this itemhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85046699837&doi=10.1073%2fpnas.1800550115&partnerID=40&md5=aaf5156a4fcc03b623f20abb342d1b99; http://hdl.handle.net/10713/9080