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Published on: August 8, 2012

Tumor-specific T cells signal tumor destruction via the lymphotoxin beta receptor

Hauke Winter1, Natasja K van den Engel, Christian H Poehlein

  • 1Laboratory of Cancer Immunobiology, Robert W, Franz Cancer Research Center, Earle A, Chiles Research Institute, Providence Portland Medical Center, Portland, Oregon, USA. Hauke.Winter@med.uni-muenchen.de

Journal of Translational Medicine
|March 16, 2007
PubMed
Abstract

Insights

Lymphotoxin-alpha (LT-alpha) from effector T cells promotes anti-tumor immunity by stimulating tumor cells to attract macrophages. This interaction, mediated by LT-beta receptor signaling, enhances the therapeutic efficacy of certain T cell therapies.

Area of Science:

  • Immunology
  • Cancer Biology
  • Molecular Biology

Background:

  • Previous studies demonstrated that effector T cells lacking perforin (PKO), IFN-gamma (GKO), or both (PKO/GKO) could mediate regression of B16BL6-D5 pulmonary metastases.
  • Tumor necrosis factor (TNF) receptor signaling was identified as critical for this tumor regression.

Purpose of the Study:

  • To investigate the role of lymphotoxin-alpha (LT-alpha) as a potential effector molecule produced by tumor-specific effector T cells.
  • To elucidate the mechanism by which LT-alpha contributes to anti-tumor activity.

Main Methods:

  • Effector T cells were generated from wild-type (wt), GKO, LT-alpha deficient (LKO), or PKO/GKO mice.
  • Therapeutic efficacy was assessed in D5 pulmonary metastases models with or without LT-beta receptor-Fc fusion protein or anti-IFN-gamma antibody.
  • Chemokine production by D5 tumor cells was analyzed using ELISA, RT-PCR, and chemotaxis assays.

Main Results:

  • Effector T cells from wt, GKO, and PKO/GKO mice expressed ligands for the LT-beta receptor (LT-betaR), which is constitutively expressed by D5 tumor cells.
  • Blocking LT-betaR signaling abrogated the therapeutic efficacy of GKO and PKO/GKO effector T cells, but not wt cells.
  • While LT-alpha did not directly induce apoptosis of D5 tumor cells in vitro, it stimulated D5 cells to secrete chemokines that promoted macrophage migration.

Conclusions:

  • LT-alpha expression by effector T cells contributes to anti-tumor activity, particularly through LT-betaR signaling on tumor cells.
  • LT-alpha induces tumor cells to secrete chemokines, attracting macrophages, suggesting a model where LT-alpha facilitates innate effector cell infiltration.
  • This mechanism provides a potential explanation for the infiltration of innate immune cells observed during tumor regression mediated by effector T cells.

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