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Macrophage-derived chemokine gene transfer results in tumor regression in murine lung carcinoma model through efficient induction of antitumor immunity

Gene Therapy volume 9, pages 793–803 (2002)Cite this article

Abstract

Chemokine gene transfer represents a promising approach in the treatment of malignancies. Macrophage-derived chemokine (MDC) (CCL22) belongs to the CC chemokine family and is a strong chemoattractant for dendritic cells (DC), NK cells and T cells. Using adenoviral vectors, human MDC gene was transferred in vivo to investigate its efficacy to induce an antitumor response and to determine the immunologic mechanisms involved. We observed that intratumoral injection of recombinant adenovirus encoding human MDC (AdMDC) resulted in marked tumor regression in a murine model with pre-established subcutaneous 3LL lung carcinoma and induced significant CTL activity. The antitumor response was demonstrated to be CD4+ T cell- and CD8+ T cell-dependent. Administration of AdMDC induced chemoattraction of DC to the tumor site, facilitated DC migration to draining lymph nodes or spleen, and finally activated DC to produce high levels of IL-12. Furthermore, a significant increase of IL-4 production within the tumors was observed early after the AdMDC administration and was followed by the increase of IL-12 and IL-2 production. The levels of IL-2, IL-12 and IFN-γ in serum, lymph nodes and spleen were also found to be higher in mice treated with AdMDC as compared with that in AdLacZ- or PBS-treated mice. The antitumor response induced by AdMDC was markedly impaired in IL-4 knockout mice, suggesting an important role of IL-4 in the induction of antitumor immunity by MDC. These results suggest that MDC gene transfer might elicit significant antitumor effects through efficient induction of antitumor immunity and might be of therapeutic potentials for cancer.

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Acknowledgements

This work was supported by grants from the TRAPOYT, National Natural Science Foundation of China (30/2/002, 30028022) and National Key Basic Research Program of China(2001CB510002). We thank Dr Zhenglong Yuan, Dr Zhenhong Guo, Dr Rui Zhang and Dr Hongmin Li for their expert technical assistance.

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Author notes

  1. X Cao

    Present address: Division de Recherche Chirurgicale et Centre de Thérapie Génique, CHUV, Pavillons 3 et 4, Lausanne, CH-1011, Switzerland

  2. J Guo, B Wang and E Regulier: The first two authors contributed equally to this work

Authors and Affiliations

  1. Institute of Immunology, Second Military Medical University, Shanghai, P.R. China

    J Guo, M Zhang, T Chen, Y Yu, Z Qin, DW Ju & X Cao

  2. Jinan General Hospital of PLA, P.R. China

    B Wang

  3. TRANSGENE SA, Strasbourg, France

    E Regulier & HE Homann

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Guo, J., Wang, B., Zhang, M. et al. Macrophage-derived chemokine gene transfer results in tumor regression in murine lung carcinoma model through efficient induction of antitumor immunity. Gene Ther 9, 793–803 (2002). https://doi.org/10.1038/sj.gt.3301688

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