Modification of dendritic cells with interferon-gamma-inducible protein-10 gene to enhance vaccine potency.
BACKGROUND
Dendritic cell (DC)-based vaccines have become a promising modality in cancer immunotherapy. However, their ability to initiate tumor antigen-specific T cell immunity is limited in various negative-feedback mechanisms. The rapid down-regulation of chemokines, such as the interferon inducible protein of 10 kDa (IP-10), which chemoattracts activated antigen-specific CD8+ T cells, would represent negative-feedback regulation. Therefore, we attempted to improve DC vaccine potency by introducing the IP-10 gene retrovirally aiming to replenish the chemoattractive activity of DCs.


METHODS
We introduced IP-10 gene into DC2.4 cells, referred to as DC-IP10, using a retroviral system. Nonsecretable mIP-10-expressing DCs (DC-mIP10) were also prepared to evaluate the effects of secretion in IP-10-mediated modulation of DC biology. Additionally, in vitro and in vivo activation of antigen-specific T lymphocytes and in vivo anti-tumor effects induced by DC-IP10 or DC-mIP10 were determined.


RESULTS
The modification of DC2.4 cells with the IP-10 gene resulted in the secretion of functionally chemoattractive IP-10 and, unexpectedly, a significant up-regulation of surface expression in co-stimulatory molecules, such as CD40 and CD80, compared to that of DCs with vector control (DC-no insert). DC-mIP10 also displayed the partially matured phenotypes but failed to recruit antigen-specific T cells in an in vitro cell culture system. Consistently, DC-IP10 generated more tumor antigen-specific CD8+ T cells and stronger anti-tumor effects in vaccinated mice than did control DCs and DC-mIP10.


CONCLUSIONS
The results obtained provide the groundwork for a future clinical translation of the chemokine-based genetic modification of DCs to increase their vaccine potency.
Kang
Tae Heung
TH
Laboratory of Infection and Immunology, Graduate School of Medicine, Korea University, Seoul, South Korea.
Bae
Hyun Cheol
HC
Kim
Seok-Ho
SH
Seo
Su Hong
SH
Son
Sang Wook
SW
Choi
Eun Young
EY
Seong
Seung-Yong
SY
Kim
Tae Woo
TW
D000818:Animals; D018122:B7-1 Antigen / Q000096:biosynthesis; D019013:CD40 Antigens / Q000096:biosynthesis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology* / Q000378:metabolism / Q000627:therapeutic use; D018929:Cell Culture Techniques; D002460:Cell Line; D054357:Chemokine CXCL10 / Q000096:biosynthesis* / Q000235:genetics* / Q000276:immunology; D002630:Chemotactic Factors / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D005260:Female; D005822:Genetic Vectors; D006801:Humans; D008175:Lung Neoplasms / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D008213:Lymphocyte Activation; D051379:Mice; D012190:Retroviridae; D014161:Transduction, Genetic; D015854:Up-Regulation
D018122:B7-1 Antigen; D019013:CD40 Antigens; D019496:Cancer Vaccines; D054357:Chemokine CXCL10; D002630:Chemotactic Factors