Enhancing antimelanoma immune responses through apoptosis.
We examined the feasibility of using tumor apoptosis at accessible sites to enhance antimelanoma immune responses in a model of spontaneous canine melanoma. We show that priming peripheral blood mononuclear cells with apoptotic melanoma cells significantly enhanced autologous and allogeneic lymphokine-activated killing of tumor cells. Since various pathways required for intrinsic apoptosis are often inactivated in melanoma, we used Fas ligand (FasL) overexpression to promote extrinsic apoptosis. FasL induced apoptosis in five of six cell lines. Each of the susceptible lines, but not the resistant one, expressed Fas mRNA. In addition, direct intratumoral administration of FasL DNA to tumor-bearing dogs was safe, with no adverse events reported over 7 days of observation. A reduction of tumor burden was seen in three of five dogs treated. The reduction of tumor volume was correlated with Fas expression by the tumors, although one dog with a Fas-negative tumor survived for 82 weeks after treatment. Our data show that overexpression of FasL is suitable to promote apoptosis of Fas(+) melanomas, and support the notion that priming immune responder cells with apoptotic tumor cells may enhance antitumor responses. The results also suggest that intratumoral administration of FasL offers a safe route for therapeutic gene delivery.
Bianco
Stacie R
SR
Center for Cancer Causation and Prevention, AMC Cancer Research Center and Donald Monk Cancer Research Foundation, Denver, Colorado 80214, USA.
Sun
Juan
J
Fosmire
Susan P
SP
Hance
Kenneth
K
Padilla
Marcia L
ML
Ritt
Michelle G
MG
Getzy
David M
DM
Duke
Richard C
RC
Withrow
Stephen J
SJ
Lana
Susan
S
Matthiesen
David T
DT
Dow
Steven W
SW
Bellgrau
Donald
D
Cutter
Gary R
GR
Helfand
Stuart C
SC
Modiano
Jaime F
JF
D000818:Animals; D017209:Apoptosis; D004283:Dog Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology* / Q000628:therapy; D004285:Dogs; D053222:Fas Ligand Protein; D015316:Genetic Therapy; D007167:Immunotherapy; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008545:Melanoma / Q000276:immunology / Q000473:pathology / Q000628:therapy* / Q000662:veterinary*; D008562:Membrane Glycoproteins / Q000009:adverse effects / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins