Gene transfer of Fas ligand induces tumor regression in vivo.

The Fas-Fas ligand (FasL) system plays an important role in the induction of lymphoid apoptosis and has been implicated in the suppression of immune responses. Herein, we report that gene transfer of FasL inhibits tumor cell growth in vivo. Although such inhibition is expected in Fas+ tumor cell lines, marked regression was unexpectedly observed after FasL gene transfer into the CT26 colon carcinoma that does not express Fas. Infection by an adenoviral vector encoding FasL rapidly eliminated tumor masses in the Fas+ Renca tumor by inducing cell death, whereas the elimination of Fas- CT26 cells was mediated by inflammatory cells. Analysis of human malignancies revealed Fas, but not FasL, expression in a majority of tumors and susceptibility to FasL in most Fas+ cell lines. These findings suggest that gene transfer of FasL generates apoptotic responses and induces potent inflammatory reactions that can be used to induce the regression of malignancies.

[1]  G. Nabel,et al.  Inhibition of the alloantibody response by CD95 ligand , 1997, Nature Medicine.

[2]  D. Hanahan,et al.  Fas ligand expression in islets of Langerhans does not confer immune privilege and instead targets them for rapid destruction , 1997, Nature Medicine.

[3]  A. Chinnaiyan,et al.  The inhibition of pro-apoptotic ICE-like proteases enhances HIV replication , 1997, Nature Medicine.

[4]  K. Okumura,et al.  Antitumor effect of locally produced CD95 ligand , 1997, Nature Medicine.

[5]  P. Galle,et al.  Lymphocyte apoptosis induced by CD95 (APO–1/Fas) ligand–expressing tumor cells — A mechanism of immune evasion? , 1996, Nature Medicine.

[6]  J. Tschopp,et al.  Melanoma Cell Expression of Fas(Apo-1/CD95) Ligand: Implications for Tumor Immune Escape , 1996, Science.

[7]  F. Shanahan,et al.  The Fas counterattack: Fas-mediated T cell killing by colon cancer cells expressing Fas ligand , 1996, The Journal of experimental medicine.

[8]  P. Kiener,et al.  Differential expression of Fas (CD95) and Fas ligand on normal human phagocytes: implications for the regulation of apoptosis in neutrophils , 1996, The Journal of experimental medicine.

[9]  C. Stoeckert,et al.  Prevention of Islet Allograft Rejection with Engineered Myoblasts Expressing FasL in Mice , 1996, Science.

[10]  A. H. Drummond,et al.  Fas ligand in human serum , 1996, Nature Medicine.

[11]  E. Lacy,et al.  Th1 CD4+ lymphocytes delete activated macrophages through the Fas/APO-1 antigen pathway. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[12]  D. Green,et al.  Fas Ligand-Induced Apoptosis as a Mechanism of Immune Privilege , 1995, Science.

[13]  D. Bellgrau,et al.  A role for CD95 ligand in preventing graft rejection , 1995, Nature.

[14]  E. Nabel,et al.  The p21 cyclin–dependent kinase inhibitor suppresses tumorigenicity in vivo , 1995, Nature Medicine.

[15]  James M. Wilson,et al.  Clearance of adenovirus-infected hepatocytes by MHC class I-restricted CD4+ CTLs in vivo. , 1995, Journal of immunology.

[16]  S. Nagata,et al.  The Fas death factor , 1995, Science.

[17]  P. Krammer,et al.  Autocrine T-cell suicide mediated by APO-1/(Fas/CD95) , 1995, Nature.

[18]  S. Ju,et al.  Fas(CD95)/FasL interactions required for programmed cell death after T-cell activation , 1995, Nature.

[19]  Seamus J. Martin,et al.  Cell-autonomous Fas (CD95)/Fas-ligand interaction mediates activation-induced apoptosis in T-cell hybridomas , 1995, Nature.

[20]  N. Lalwani,et al.  Fas ligation triggers apoptosis in macrophages but not endothelial cells , 1994, European journal of immunology.

[21]  E. Nabel,et al.  Gene therapy for vascular smooth muscle cell proliferation after arterial injury. , 1994, Science.

[22]  Takashi Suda,et al.  Molecular cloning and expression of the fas ligand, a novel member of the tumor necrosis factor family , 1993, Cell.

[23]  S. Nagata,et al.  Lethal effect of the anti-Fas antibody in mice , 1993, Nature.

[24]  Atsushi Hase,et al.  The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis , 1991, Cell.

[25]  B. Vogelstein,et al.  Interleukin-2 production by tumor cells bypasses T helper function in the generation of an antitumor response , 1990, Cell.

[26]  E. Butcher,et al.  Ly‐6C is a monocyte/macrophage and endothelial cell differentiation antigen regulated by interferon‐gamma , 1988, European journal of immunology.

[27]  R. Custer,et al.  A severe combined immunodeficiency mutation in the mouse , 1983, Nature.

[28]  J. Roder,et al.  The beige mutation in the mouse selectively impairs natural killer cell function , 1979, Nature.

[29]  J. Damme.  Interleukin-8 and related chemotactic cytokines , 1994 .

[30]  B. Dewald,et al.  Interleukin-8 and related chemotactic cytokines--CXC and CC chemokines. , 1994, Advances in immunology.

[31]  B. Giovanella,et al.  The nude mouse in cancer research. , 1985, Advances in cancer research.