title: Tumor-specific T cells signal tumor destruction via the lymphotoxin beta receptor.
abstract: BACKGROUND
  Previously, we reported that adoptively transferred perforin k/o (PKO), and IFN-gamma k/o (GKO), or perforin/IFN-gamma double k/o (PKO/GKO) effector T cells mediated regression of B16BL6-D5 (D5) pulmonary metastases and showed that TNF receptor signaling played a critical role in mediating tumor regression. In this report we investigated the role of lymphotoxin-alpha (LT-alpha) as a potential effector molecules of tumor-specific effector T cells.
  
  
  METHODS
  Effector T cells were generated from tumor vaccine-draining lymph node (TVDLN) of wt, GKO, LT-alpha deficient (LKO), or PKO/GKO mice and tested for their ability to mediate regression of D5 pulmonary metastases in the presence or absence of LT-betaR-Fc fusion protein or anti-IFN-gamma antibody. Chemokine production by D5 tumor cells was determined by ELISA, RT-PCR and Chemotaxis assays.
  
  
  RESULTS
  Stimulated effector T cells from wt, GKO, or PKO/GKO mice expressed ligands for LT-beta receptor (LT-betaR). D5 tumor cells were found to constitutively express the LT-betaR. Administration of LT-betaR-Fc fusion protein completely abrogated the therapeutic efficacy of GKO or PKO/GKO but not wt effector T cells (p < 0.05). Consistent with this observation, therapeutic efficacy of effector T cells deficient in LT-alpha, was greatly reduced when IFN-gamma production was neutralized. While recombinant LT-alpha1beta2 did not induce apoptosis of D5 tumor cells in vitro, it induced secretion of chemokines by D5 that promoted migration of macrophages.
  
  
  CONCLUSIONS
  The contribution of LT-alpha expression by effector T cells to anti-tumor activity in vivo was not discernable when wt effector T cells were studied. However, the contribution of LT-beta R signaling was identified for GKO or PKO/GKO effector T cells. Since LT-alpha does not directly induce killing of D5 tumor cells in vitro, but does stimulate D5 tumor cells to secrete chemokines, these data suggest a model where LT-alpha expression by tumor-specific effector T cells interacts via cross-linking of the LT-betaR on tumor cells to induce secretion of chemokines that are chemotactic for macrophages. While the contribution of macrophages to tumor elimination in our system requires additional study, this model provides a possible explanation for the infiltration of inate effector cells that is seen coincident with tumor regression.
authors.affiliation: Laboratory 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
authors.forename: Hauke
authors.initials: H
authors.lastname: Winter
authors.forename: Natasja K
authors.initials: NK
authors.lastname: van den Engel
authors.forename: Christian H
authors.initials: CH
authors.lastname: Poehlein
authors.forename: Rudolf A
authors.initials: RA
authors.lastname: Hatz
authors.forename: Bernard A
authors.initials: BA
authors.lastname: Fox
authors.forename: Hong-Ming
authors.initials: HM
authors.lastname: Hu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D045744:Cell Line, Tumor; D018925:Chemokines / Q000096:biosynthesis; D002633:Chemotaxis / Q000187:drug effects / Q000276:immunology; D005260:Female; D006801:Humans; D016219:Immunotherapy, Adoptive; D007371:Interferon-gamma / Q000276:immunology; D008024:Ligands; D053361:Lymphotoxin alpha1, beta2 Heterotrimer / Q000494:pharmacology; D053259:Lymphotoxin beta Receptor / Q000276:immunology*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000276:immunology*; D009500:Neutralization Tests; D011961:Receptors, Fc / Q000276:immunology; D011994:Recombinant Proteins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000473:pathology*; D016896:Treatment Outcome
chemical_list: D018925:Chemokines; D008024:Ligands; D053361:Lymphotoxin alpha1, beta2 Heterotrimer; D053259:Lymphotoxin beta Receptor; D011961:Receptors, Fc; D011994:Recombinant Proteins; D007371:Interferon-gamma