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Immunological tumor destruction in a murine melanoma model by targeted LTα independent of secondary lymphoid tissue

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Abstract

Background

We previously demonstrated that targeting lymphotoxin α (LTα) to the tumor evokes its immunological destruction in a syngeneic B16 melanoma model. Since treatment was associated with the induction of peritumoral tertiary lymphoid tissue, we speculated that the induced immune response was initiated at the tumor site.

Methods and results

In order to directly test this notion, we analyzed the efficacy of tumor targeted LTα in LTα knock-out (LTα−/−) mice which lack peripheral lymph nodes. To this end, we demonstrate that tumor-targeted LTα mediates the induction of specific T-cell responses even in the absence of secondary lymphoid organs. In addition, this effect is accompanied by the initiation of tertiary lymphoid tissue at the tumor site in which B and T lymphocytes are compartmentalized in defined areas and which harbor expanded numbers of tumor specific T cells as demonstrated by in situ TRP-2/Kb tetramer staining. Mechanistically, targeted LTα therapy seems to induce changes at the tumor site which allows a coordinated interaction of immune competent cells triggering the induction of tertiary lymphoid tissue.

Conclusion

Thus, our data demonstrate that targeted LTα promotes an accelerated immune response by enabling the priming of T cells at the tumor site.

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Abbreviations

APCs:

Antigen presenting cells

HEV:

High endothelial venules

LTα:

Lymphotoxin α

LTα−/− :

LTα knock-out

LTβR:

LTβ receptor

sLTα:

Soluble lymphotoxin α

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Acknowledgments

We thank Carrie Dolman, Eva Baumann, Katrin Mueller-Blech and Claudia Siedel for excellent technical assistance; Susan Schellworth for animal care. This work was supported by Deutsche Forschungsgemeinschaft grant Be 1394/5-2 and grant SFP1330 from EMD-Lexigen Research Center, Bedford, MA. (R.X., R.A.R.). D. S. was supported by the Deutsche Krebshilfe.

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Authors and Affiliations

  1. Department of Dermatology, Julius-Maximilians-University, University of Würzburg, Josef-Schneider-Str. 2, Buildg. D8, 97080, Würzburg, Germany

    David Schrama, Heike Voigt, Andreas O. Eggert & Jürgen C. Becker

  2. The Scripps Research Institute, La Jolla, CA, 92037, USA

    Rong Xiang, He Zhou & Ralph A. Reisfeld

  3. Division of immunology, The Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands

    Ton N. M. Schumacher

  4. Tumor Immunology Group, Institute of Cancer Biology, Danish Cancer Society, 2100, Copenhagen, Denmark

    Mads H. Andersen & Per thor Straten

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  1. David Schrama
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Correspondence to David Schrama.

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Schrama, D., Voigt, H., Eggert, A.O. et al. Immunological tumor destruction in a murine melanoma model by targeted LTα independent of secondary lymphoid tissue. Cancer Immunol Immunother 57, 85–95 (2008). https://doi.org/10.1007/s00262-007-0352-x

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  • DOI: https://doi.org/10.1007/s00262-007-0352-x

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