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

Cancer Immunol Immunother. 2008 Jan;57(1):85-95. doi: 10.1007/s00262-007-0352-x. Epub 2007 Jun 29.

Abstract

Background: We previously demonstrated that targeting lymphotoxin alpha (LTalpha) 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 LTalpha in LTalpha knock-out (LTalpha(-/-)) mice which lack peripheral lymph nodes. To this end, we demonstrate that tumor-targeted LTalpha 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/K(b) tetramer staining. Mechanistically, targeted LTalpha 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 LTalpha promotes an accelerated immune response by enabling the priming of T cells at the tumor site.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Gangliosides / immunology
  • Humans
  • Immunohistochemistry
  • Lymphocyte Activation / immunology
  • Lymphocytes, Tumor-Infiltrating
  • Lymphoid Tissue / cytology
  • Lymphoid Tissue / immunology*
  • Lymphotoxin-alpha / immunology*
  • Lymphotoxin-alpha / therapeutic use*
  • Melanoma, Experimental / immunology
  • Melanoma, Experimental / therapy*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Recombinant Fusion Proteins / immunology
  • Recombinant Fusion Proteins / therapeutic use
  • T-Lymphocytes / immunology

Substances

  • Gangliosides
  • Lymphotoxin-alpha
  • Recombinant Fusion Proteins
  • sialogangliosides