Increased immunogenicity of surviving tumor cells enables cooperation between liposomal doxorubicin and IL-18.
BACKGROUND
Liposomal doxorubicin (Doxil) is a cytotoxic chemotherapy drug with a favorable hematologic toxicity profile. Its active drug, doxorubicin, has interesting immunomodulatory properties. Here, the effects of Doxil on surviving tumor cell immunophenotype were investigated.


METHODS
Using ID8 murine ovarian cancer cells, the immunomodulatory effects of Doxil were studied by measuring its impact on ovarian cancer cell expression of MHC class-I and Fas, and susceptibility to immune attack in vitro. To evaluate the ability of Doxil to cooperate with cancer immunotherapy, the interaction between Doxil and Interleukin 18 (IL-18), a pleiotropic immunostimulatory cytokine, was investigated in vivo in mice bearing ID8-Vegf tumors.


RESULTS
While Doxil killed ID8 tumor cells in a dose-dependent manner, tumor cells escaping Doxil-induced apoptosis upregulated surface expression of MHC-I and Fas, and were sensitized to CTL killing and Fas-mediated death in vitro. We therefore tested the hypothesis that the combination of immunotherapy with Doxil provides positive interactions. Combination IL-18 and Doxil significantly suppressed tumor growth compared with either monotherapy in vivo and uniquely resulted in complete tumor regression and long term antitumor protection in a significant proportion of mice.


CONCLUSIONS
These data demonstrate that Doxil favorably changes the immunophenotype of a large fraction of the tumor that escapes direct killing thus creating an opportunity to expand tumor killing by immunotherapy, which can be capitalized through addition of IL-18 in vivo.
Alagkiozidis
Ioannis
I
Department of Obstetrics and Gynecology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Facciabene
Andrea
A
Carpenito
Carmine
C
Benencia
Fabian
F
Jonak
Zdenka
Z
Adams
Sarah
S
Carroll
Richard G
RG
Gimotty
Phyllis A
PA
Hammond
Rachel
R
Danet-Desnoyers
Gwen-äel
GÄ
June
Carl H
CH
Powell
Daniel J
DJ
Coukos
George
G
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000276:immunology / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D004317:Doxorubicin / Q000276:immunology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D020382:Interleukin-18 / Q000276:immunology / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D015996:Survival Rate
D000903:Antibiotics, Antineoplastic; D020382:Interleukin-18; D004317:Doxorubicin