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The Journal of Immunology, 1999, 163: 4886-4893.
Copyright © 1999 by The American Association of Immunologists

A "Stealth Effect": Adenocarcinoma Cells Engineered to Express TRAIL Elude Tumor-Specific and Allogeneic T Cell Reactions1

Mirella Giovarelli2,*, Piero Musiani{dagger}, Gianni Garotta§, Reinhard Ebner§, Emma Di Carlo{dagger}, Yunsoo Kim§, Paola Cappello*, Laura Rigamonti*, Paola Bernabei*, Francesco Novelli*, Andrea Modesti{ddagger}, Anna Coletti{ddagger}, Ann Kim Ferrie§, Pier-Luigi Lollini*, Steve Ruben§, Theodora Salcedo§ and Guido Forni*

* Department of Clinical and Biological Sciences, University of Turin, Orbassano, Italy; {dagger} Department of Oncology and Neuroscience, University of Chieti, Chieti, Italy; {ddagger} Department of Experimental Medicine and Biochemistry, University of Tor Vergata, Rome, Italy; and § Human Genome Sciences, Inc., Rockville, MD 20850

BALB/c mammary adenocarcinoma cells engineered to express TNF-related apoptosis-inducing ligand (TRAIL)/APO-2 ligand (APO-2L) on their membrane (TSA-TRAIL) grow with kinetics similar to that of parental cells (TSA-pc) in vitro and in nu/nu mice. In contrast, TSA-TRAIL cells grow faster than TSA-pc in normal BALB/c mice. In DBA/2 mice, which differ from BALB/c mice at minor histocompatibility Ags, they also grow faster and display a higher percentage of tumor takes than TSA-pc. In fully histoincompatible C57BL/6 (B6) mice, TSA-TRAIL cells form evident tumors that are slowly rejected by most mice, but outgrow in a few. In contrast, TSA-pc cells are rejected at once by B6 mice. Since TRAIL/APO-2L induces apoptosis by interacting with a variety of specific receptors, this rapid growth in both syngeneic and allogeneic mice may be the result of an immunosuppressive mechanism. The following evidence supports this hypothesis: 1) TSA-TRAIL cells overcome the strong immunity against TSA-pc cells elicited in BALB/c mice by preimmunization with TSA cells engineered to release IL-4; 2) their rejection by B6 mice does not prime a CTL-mediated memory; 3) thymidine uptake by T lymphocytes unstimulated or stimulated by allogeneic cells is inhibited when TSA-TRAIL cells are added as third party cells; 4) CTL kill TSA-pc but not TSA-TRAIL cells in 48-h assays; and 5) activated lymphocytes interacting with TSA-TRAIL cells in vivo and in vitro undergo apoptosis.




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