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null Mice1
* State University of New York, Department of Microbiology and Immunology and the Witebsky Center for Microbial Pathogenesis and Immunology, University at Buffalo, Buffalo, NY 14214;
Buffalo Thoracic Surgical Associates, Buffalo, NY 14209;
Therapyx, Inc., Buffalo, NY 14214;
The Jackson Laboratory, Bar Harbor, ME 04609; and
¶ Department of Pathology, Roswell Park Cancer Institute, Buffalo, NY 14263
Non-disrupted pieces of primary human lung tumor implanted into NOD-scid IL2R
null mice consistently result in successful xenografts in which tissue architecture, including tumor-associated leukocytes, stromal fibroblasts, and tumor cells are preserved for prolonged periods with limited host-vs-graft interference. Human CD45+ tumor-associated leukocytes within the xenograft are predominantly CD3+ T cells with fewer CD138+ plasma cells. The effector memory T cells that had been shown to be quiescent in human lung tumor microenvironments can be activated in situ as determined by the production of human IFN- in response to exogenous IL-12. Plasma cells remain functional as evidenced by production of human Ig. Significant levels of human IFN- and Ig were detected in sera from xenograft-bearing mice for up to 9 wk postengraftment. Tumor-associated T cells were found to migrate from the microenvironment of the xenograft to the lung, liver, and primarily the spleen. At 8 wk postengraftment, a significant portion of cells isolated from the mouse spleens were found to be human CD45+ cells. The majority of CD45+ cells were CD3+ and expressed a phenotype consistent with an effector memory T cell, consisting of CD4+ or CD8+ T cells that were CD45RO+, CD44+, CD62L–, and CD25–. Following adoptive transfer into non-tumor bearing NOD-scid IL2Rnull mice, these human T cells were found to expand in the spleen, produce IFN-, and maintain an effector memory phenotype. We conclude that the NOD-scid IL2Rnull tumor xenograft model provides an opportunity to study tumor and tumor-stromal cell interactions in situ for prolonged periods.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by U.S. Public Health Service Grants, National Institutes of Health Grant R01-CA10897 (to R.B.B.), the John R. Oishei Foundation, National Institutes of Health Research Training Grant T32 AI1007614-07 (to M.R.S.-A.), and the Jackson Lab Cancer Core Grant CA34196 (to L.D.S.)
2 M.R.S.-A. and G.F.S. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Richard B. Bankert, Department of Microbiology and Immunology, 138 Farber Hall, State University of New York, 3435 Main Street, Buffalo, NY 14214. E-mail address: rbankert{at}buffalo.edu
4 Abbreviations used in this paper: mIL-7, murine IL-7; XGVHD, xenoreactive graft vs host disease.
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