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Human CD4⁺ Effector Memory T Cells Persisting in the Microenvironment of Lung Cancer Xenografts Are Activated by Local Delivery of IL-12 to Proliferate, Produce IFN-, and Eradicate Tumor Cells¹

Lori Broderick^*, Sandra J. Yokota^*, Joshua Reineke, Edith Mathiowitz, Carleton C. Stewart, Maurice Barcos, Raymond J. Kelleher, Jr.^* and Richard B. Bankert^2,*

^* Department of Microbiology and Immunology, State University of New York, Buffalo, NY 14214; Department of Molecular Pharmacology, Physiology, and Biotechnology, Brown University, Providence, RI 02912; and Departments of Flow Cytometry and Pathology, Roswell Park Cancer Institute, Buffalo, NY 14263

The implantation of small pieces of human primary lung tumor biopsy tissue into SCID mice results in a viable s.c. xenograft in which the tissue architecture, including tumor-associated leukocytes, tumor cells, and stromal cells, is preserved in a functional state. By monitoring changes in tumor volume, gene expression patterns, cell depletion analysis, and the use of function-blocking Abs, we previously established in this xenograft model that exogenous IL-12 mobilizes human tumor-associated leukocytes to kill tumor cells in situ by indirect mechanisms that are dependent upon IFN-. In this study immunohistochemistry and FACS characterize the early cellular events in the tumor microenvironment induced by IL-12. By 5 days post-IL-12 treatment, the constitutively present human CD45⁺ leukocytes have expanded and infiltrated into tumor-rich areas of the xenograft. Two weeks post-treatment, there is expansion of the human leukocytes and complete effacement of the tumor compared with tumor progression and gradual loss of most human leukocytes in control-treated xenografts. Immunohistochemical analyses reveal that the responding human leukocytes are primarily activated or memory T cells, with smaller populations of B cells, macrophages, plasma cells, and plasmacytoid dendritic cells capable of producing IFN-. The predominant cell population was also characterized by FACS and was shown to have a phenotype consistent with a CD4⁺ effector memory T cell. We conclude that quiescent CD4⁺ effector memory T cells are present within the tumor microenvironment of human lung tumors and can be reactivated by the local and sustained release of IL-12 to proliferate and secrete IFN-, leading to tumor cell eradication.

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