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-gamma, and eradicate tumor cells

• Published in: The Journal of immunology (1950) Vol. 174; no. 2; pp. 898 - 906
• Main Authors: Broderick, Lori, Yokota, Sandra J, Reineke, Joshua, Mathiowitz, Edith, Stewart, Carleton C, Barcos, Maurice, Kelleher, Jr, Raymond J, Bankert, Richard B
• Format: Journal Article
• Language: English
• Published: United States 15-01-2005
• Subjects: Animals; Carcinoma, Non-Small-Cell Lung - immunology; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; Carcinoma, Non-Small-Cell Lung - prevention & control; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CD4-Positive T-Lymphocytes - pathology; Cell Proliferation; Dendritic Cells - pathology; Humans; Immunologic Memory; Immunophenotyping; Injections, Intralesional; Interferon-gamma - biosynthesis; Interferon-gamma - blood; Interleukin-12 - administration & dosage; Interleukin-12 - therapeutic use; Killer Cells, Natural - pathology; Leukocyte Common Antigens - biosynthesis; Leukocytes - pathology; Lung Neoplasms - immunology; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Lung Neoplasms - prevention & control; Lymphocyte Activation - immunology; Mice; Mice, SCID; Recombinant Proteins - administration & dosage; T-Lymphocyte Subsets - pathology; Transplantation, Heterologous - immunology; Transplantation, Heterologous - pathology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.174.2.898

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-gamma. 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-alpha. 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-gamma, leading to tumor cell eradication.