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The Journal of Immunology, 2004, 173: 7209-7216.
Copyright © 2004 by The American Association of Immunologists

Vaccine-Stimulated, Adoptively Transferred CD8+ T Cells Traffic Indiscriminately and Ubiquitously while Mediating Specific Tumor Destruction1

Douglas C. Palmer*,2,3, Sanjeeve Balasubramaniam3,*, Ken-ichi Hanada*, Claudia Wrzesinski*, Zhiya Yu*, Shahram Farid*, Marc R. Theoret{dagger}, Leroy N. Hwang*, Christopher A. Klebanoff{dagger}, Luca Gattinoni*, Allan L. Goldstein{ddagger}, James C. Yang* and Nicholas P. Restifo*

* National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; {dagger} Howard Hughes Medical Institute-National Institutes of Health, Research Scholars Program, Bethesda, MD 20815; and {ddagger} Department of Biochemistry and Molecular Biology, The George Washington University School of Medicine and Health Sciences, Washington, D.C. 20037

It has been suggested that antitumor T cells specifically traffic to the tumor site, where they effect tumor destruction. To test whether tumor-reactive CD8+ T cells specifically home to tumor, we assessed the trafficking of gp100-specific pmel-1 cells to large, vascularized tumors that express or do not express the target Ag. Activation of tumor-specific CD8+ pmel-1 T cells with IL-2 and vaccination with an altered peptide ligand caused regression of gp100-positive tumors (B16), but not gp100-negative tumors (methylcholanthrene 205), implanted on opposing flanks of the same mouse. Surprisingly, we found approximately equal and very large numbers of pmel-1 T cells (>25% of all lymphocytes) infiltrating both Ag-positive and Ag-negative tumors. We also found evidence of massive infiltration and proliferation of activated antitumor pmel-1 cells in a variety of peripheral tissues, including lymph nodes, liver, spleen, and lungs, but not peripheral blood. Most importantly, evidence for T cell function, as measured by production of IFN-{gamma}, release of perforin, and activation of caspase-3 in target cells, was confined to Ag-expressing tumor. We thus conclude that CD8+ T cell-mediated destruction of tumor is the result of specific T cell triggering at the tumor site. The ability to induce ubiquitous homing and specific tumor destruction may be important in the case of noninflammatory metastatic tumor foci.




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