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.
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.
Broderick
Lori
L
Department of Microbiology and Immunology, State University of New York, Buffalo, NY 14214, USA.
Yokota
Sandra J
SJ
Reineke
Joshua
J
Mathiowitz
Edith
E
Stewart
Carleton C
CC
Barcos
Maurice
M
Kelleher
Raymond J
RJ
Bankert
Richard B
RB
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000473:pathology; D006801:Humans; D007156:Immunologic Memory; D016130:Immunophenotyping; D015552:Injections, Intralesional; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000097:blood; D018664:Interleukin-12 / Q000008:administration & dosage* / Q000627:therapeutic use; D007694:Killer Cells, Natural / Q000473:pathology; D017493:Leukocyte Common Antigens / Q000096:biosynthesis; D007962:Leukocytes / Q000473:pathology; D008175:Lung Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D016513:Mice, SCID; D011994:Recombinant Proteins / Q000008:administration & dosage; D016176:T-Lymphocyte Subsets / Q000473:pathology; D014183:Transplantation, Heterologous / Q000276:immunology* / Q000473:pathology
D011994:Recombinant Proteins; D018664:Interleukin-12; D007371:Interferon-gamma; D017493:Leukocyte Common Antigens