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EBV-Induced Molecule 1 Ligand Chemokine (ELC/CCL19) Promotes IFN--Dependent Antitumor Responses in a Lung Cancer Model

Sven Hillinger^*, Seok-Chul Yang^*, Li Zhu^*,, Min Huang^*,, Russell Duckett, Kimberly Atianzar^*, Raj K. Batra^*,, Robert M. Strieter^*,, Steven M. Dubinett^*,, and Sherven Sharma^2,*,,

^* Department of Medicine, University of California, Los Angeles Lung Cancer Research Program, and Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095; and Molecular Gene Medicine Laboratory, Veteran’s Affairs Greater Los Angeles Healthcare System, Los Angeles, CA 90073

The antitumor efficacy of EBV-induced molecule 1 ligand CC chemokine (ELC/CCL19) was evaluated in a murine lung cancer model. The ability of ELC/CCL19 to chemoattract both dendritic cells and T lymphocytes formed the rationale for this study. Compared with diluent-treated tumor-bearing mice, intratumoral injection of recombinant ELC/CCL19 led to significant systemic reduction in tumor volumes (p < 0.01). ELC/CCL19-treated mice exhibited an increased influx of CD4 and CD8 T cell subsets as well as dendritic cells at the tumor sites. These cell infiltrates were accompanied by increases in IFN-, MIG/CXCL9, IP-10/CXCL10, GM-CSF, and IL-12 but a concomitant decrease in the immunosuppressive molecules PGE₂ and TGF. Transfer of T lymphocytes from ELC/CCL19 treated tumor-bearing mice conferred the antitumor therapeutic efficacy of ELC/CCL19 to naive mice. ELC/CCL19 treated tumor-bearing mice showed enhanced frequency of tumor specific T lymphocytes secreting IFN-. In vivo depletion of IFN-, MIG/CXCL9, or IP-10/CXCL10 significantly reduced the antitumor efficacy of ELC/CCL19. These findings provide a strong rationale for further evaluation of ELC/CCL19 in tumor immunity and its use in cancer immunotherapy.

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