Introduction. Effective anti-tumor responses require both antigen presenting cells and lymphocyte effectors. Although lung cancers express tumor antigens, they are ineffective as antigen presenting cells because tumor cells often have limited expression of MHC Ags and lack co-stimulatory molecules. It has been demonstrated that local and systemic administration of chemokines as stimulators of the immune response is beneficial as potent anti-cancer strategy. Epstein Barr virus-induced molecule 1 ligand chemokine (ELC/CCL19) is a CC chemokine that strongly chemoattracts both dendritic cells (DC) and T lymphocytes. In this study we evaluated the anti-tumor efficacy of loco-regional ELC/CCL19 administration in an orthotopic model of bronchogenic carcinoma. Methods. 5x104 L1C2 and 3LL cells have been injected into the right upper pulmonary lobe of Balb/C and C57/Bl6 mice respectively. Two days after injection mice have been treated with right intraaxillar (lymph node region) injection of recombinant ELC/CCL19 (0.5μg/dose) three times per week for 2 weeks. For the evaluation of ELC/CCL19 mediated loco-regional anti-tumor responses, lungs were harvested three weeks after treatment and lung blocks as well as axillary lymph nodes assessed for H&E staining to evaluate the tumor burden and analyses of tumor infiltrating T cell subsets by flow cytometry. Tumor bearing lungs were evaluated for the production of IL-10, IL-12, GM-CSF, IFNγ, TGFβ, by ELISA and PGE2 by enzyme immunoassay (EIA) in the supernatants after an overnight culture. Results. Histological evaluation of tumor sections and axillary lymph nodes revealed extensive lymphocytic infiltration with a marked reduction in tumor growth compared to diluent controls. Flow cytometric analysis showed a significant increase in both CD4 and CD8 subsets as well as dendritic cells. However, there was a decrease in CD4+CD25+ T regulatory cells in the tumor infiltrating lymphocytes of ELC/CCL19 treated mice lungs. Lung tissue cytokine profiles showed a shift towards immunostimulatory molecules. Conclusion. These results in a clinically relevant orthotopic model of lung cancer confirm the importance of chemokines in the development of an effective anticancer-immunotherapy. Further studies are warranted to delineate the mechanisms responsible for the anti-tumor responses following ELC/CCL19 therapy for lung cancer.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]