Virology- and immunology-based gene therapy for cancer.
Current strategies for cancer gene therapy consist mainly of direct inhibition of tumor cell growth and activation of systemic host defense mechanisms. Conventional chemotherapy and radiotherapy, even considered to be temporally suppressing tumor growth, suppress immune responses; therefore, we examined potential clinical feasibility of virus-mediated tumor destruction, which can rather enhance immunity. We showed that human tumors were more susceptible to adenoviruses (Ad) in which the E1A expression was controlled by a putative tumor promoter than normal cells, and that a replication of the Ad was greater in tumor cells than in normal cells. We also demonstrated that the intratumoral injection of the Ad bearing a tumor promoter inhibited the subsequent tumor growth in vivo. The E1A expression was detected in the tumors injected with the Ad but not in non-tumorous tissues of the same mice. The Ad modified to show the regulated E1A expression is thereby oncolytic in nature. Antitumor immune responses are initiated after the acquisition of putative tumor antigen(s) by dendritic cells (DCs); therefore, enhanced antigen presentation is a crucial step for the early phase of cell-mediated immunity. Destruction of tumors can release the tumor antigens and DCs come to recognize them thereafter. We found that the stimulation of Fas expressed on DCs with Fas ligand (FasL) did not induce apoptosis of DCs but rather enhanced the antigen presentation. Activation of DCs induced production of a number of cytokines, and we showed that the interleukin-12 family secreted from tumors could induce systemic antitumor immunity. We presume that the administration of oncolytic Ad, which can destroy local tumors and subsequently make the putative tumor antigen(s) released from the tumors, stimulation of DCs with the Fas/FasL signal pathway and secretion of DCs-derived cytokines coordinately produce synergistic antitumor effects and that a combinatory application of these procedures can be a possible therapeutic strategy for cancer treatment.
Tagawa
Masatoshi
M
Division of Pathology, Chiba Cancer Center Research Institute, 666-2 Nitona, Chiba 260-8717, Japan. mtagawa@chiba-cc.jp
Kawamura
Kiyoko
K
Shimozato
Osamu
O
Ma
Guangyu
G
Li
Quanhai
Q
Suzuki
Nobuo
N
Shimada
Hideaki
H
Ochiai
Takenori
T
D017500:Adenovirus E1A Proteins / Q000737:chemistry; D017951:Antigen Presentation; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology; D053222:Fas Ligand Protein; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007158:Immunologic Techniques; D007167:Immunotherapy / Q000379:methods*; D018664:Interleukin-12 / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D008954:Models, Biological; D009369:Neoplasms / Q000628:therapy*; D048069:Tumor Necrosis Factors / Q000378:metabolism; D014773:Virology / Q000379:methods; D019014:fas Receptor / Q000096:biosynthesis
D017500:Adenovirus E1A Proteins; D016207:Cytokines; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D048069:Tumor Necrosis Factors; D019014:fas Receptor; D018664:Interleukin-12