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Kim, Kim, Choi, Jeong, Lee, Choe, Paik, and Lim: IL-12 Production and Subsequent Natural Killer Cell Activation by Necrotic Tumor Cell-loaded Dendritic Cells in Therapeutic Vaccinations
Original Article

Immune Network 2003; 3(3): 188-200.

Published online: 30 September 2003

DOI: https://doi.org/10.4110/in.2003.3.3.188

IL-12 Production and Subsequent Natural Killer Cell Activation by Necrotic Tumor Cell-loaded Dendritic Cells in Therapeutic Vaccinations

Aeyung Kim1, Kwang Dong Kim1, Seung-Chul Choi1, Moon-Jin Jeong2, Hee Gu Lee1, Yong-Kyung Choe1, Sang-Gi Paik3, Jong-Seok Lim1

1Laboratory of Cell Biology, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.

2Department of Oral Histology, College of Dentistry, Chosun University, Gwangju, Korea.

3Department of Biology, Chungnam National University, Daejeon, Korea.

Correspondence to: Jong-Seok Lim, Laboratory of Cell Biology, Korea Research Institute of Bioscience and Biotechnology, Yusung P.O. Box 115, Daejeon 305-600, Korea. (Tel) +82-42-860-4193, (Fax) +82-42-860-4593, jslim@kribb.re.kr

Copyright © 2003 The Korean Association of Immunologists

(open-access):

This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background

Immunization of dendritic cells (DCs) pulsed with tumor antigen can activate tumor-specific cytotoxic T lymphocytes (CTL) that are responsible for protection and regression. In this study, we examined whether the uptake of necrotic tumor cells could modulate DC phenotypes and whether the immunization of necrotic tumor cell-loaded DCs could elicit efficient tumor specific immune responses followed by a regression of established tumor burdens.

Methods

We prepared necrotic tumor cell-pulsed DCs for the therapeutic vaccination and investigated their phenotypic characteristics, the immune responses induced by these DCs, and therapeutic vaccine efficacy against colon carcinoma in vivo. Several parameters including phagocytosis of tumor cells, surface antigen expression, chemokine receptor expression, IL-12 production, and NK as well as CTL activation were assessed to characterize the immune response.

Results

DCs derived from mouse bone marrow efficiently phagocytosed necrotic tumor cells and after the uptake, they produced remarkably increased levels of IL-12. A decreased CCR1 and increased CCR7 expression on DCs was also observed after the tumor uptake, suggesting that antigen uptake could induce DC maturation. Furthermore, co-culturing of DCs with NK cells in vitro enhanced IL-12 production in DCs and IFN-γ production in NK cells, which was significantly dependent on IL-12 production and cell-to-cell contact. Immunization of necrotic tumor cell-loaded DCs induced cytotoxic T lymphocytes as well as NK activation, and protected mice against subsequent tumor challenge. In addition, intratumoral or contra-lateral immunization of these DCs not only inhibited the growth of established tumors, but also eradicated tumors in more than 60% of tumor-bearing mice.

Conclusion

Our data indicate that production of IL-12, chemokine receptor expression and NK as well as CTL activation may serve as major parameters in assessing the effect of tumor cell-pulsed DC vaccine. Therefore, DCs loaded with necrotic tumor cells offer a rational strategy to treat tumors and eventually lead to prolonged survival.

Keywords: Dendritic cells (DC), IL-12, NK cells, cytotoxic T lymphocytes (CTL), IFN-γ

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