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Abstract
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.
Highlights
We found 111In in liver, spleen, and lungs as well as in metastatic deposits, but it could not be determined whether live 111In-labeled T cells trafficked to these locations, or the 111In nuclide had lodged at these locations as a result of the death, phagocytosis, or target specificity of the adoptively transferred T cells [2]
We explored whether T cells with tumor specificity were able to traffic to an Ag-expressing tumor site
In our present study we found that, contrary to what was previously thought, there is a lack of Ag-dependent specificity of tumor-reactive T cells at the level of infiltration and proliferation in the tumor
Summary
Pmel-1 transgenics or C57BL/6n mice at 6 –12 wk of age were implanted s.c. with 2–5 ϫ 105 B16 melanoma cells and/or 2–5 ϫ 105 MCA-205 colon carcinoma on opposing flanks and in vivo stimulated as described previously [9]. C57BL/6n tumor-bearing mice were sublethally irradiated with 5 Gy before adoptive transfer of in vitro-activated pmel-1 splenocytes (1–2 ϫ 106 CD8ϩV13ϩ T cells) and in vivo stimulation [9]. Tumors were homogenized, pulsed with 1 M human gp10025–33 and Golgi-Stop (BD Pharmingen) for 3.5 h, stained extracellularly, permeabilized using the Cytofix/Cytoperm kit (BD Biosciences), and stained with allophycocyanin-conjugated anti-IFN-␥ mAbs (XMG1.2). Cells were permeabilized using Cytofix/Cytoperm (BD Biosciences), treated with DNase I (Sigma-Aldrich) for 1 h at 37°C, stained with FITC-, PE-, or allophycocyanin-conjugated anti-BrdU (BD Biosciences), and analyzed using FACS
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