A "stealth effect": adenocarcinoma cells engineered to express TRAIL elude tumor-specific and allogeneic T cell reactions.
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.
Giovarelli
M
M
Department of Clinical and Biological Sciences, University of Turin, Orbassano, Italy. giovarel@sluigi.unito.it
Musiani
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P
Garotta
G
G
Ebner
R
R
Di Carlo
E
E
Kim
Y
Y
Cappello
P
P
Rigamonti
L
L
Bernabei
P
P
Novelli
F
F
Modesti
A
A
Coletti
A
A
Ferrie
A K
AK
Lollini
P L
PL
Ruben
S
S
Salcedo
T
T
Forni
G
G
D000230:Adenocarcinoma / Q000235:genetics / Q000276:immunology*; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000235:genetics / Q000276:immunology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology*; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D015202:Protein Engineering; D013045:Species Specificity; D013601:T-Lymphocytes / Q000276:immunology*; D053221:TNF-Related Apoptosis-Inducing Ligand; D014407:Tumor Cells, Cultured; D019139:Tumor Escape / Q000235:genetics / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics*
D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha