Induction of antitumor immunity by combined immunogene therapy using IL-2 and IL-12 in low antigenic Lewis lung carcinoma.
Interleukin-2 (IL-2) and interleukin-12 (IL-12) are crucial cytokines that induce potent antitumor responses in a variety of animal cancer models. Although single gene transfer of either IL-2 or IL-12 exhibits limited antitumor effects, the combination of IL-2 and IL-12 has been shown to induce a stronger antitumor response and to cure tumor-bearing mice. To examine the conditions necessary for tumor rejection, we varied the local concentration of IL-2 and IL-12 by introducing these genes into Lewis lung carcinoma (LLC) cells via retroviral vectors and/or an adenoviral vector and evaluated the growth of inoculated LLC cells (5 x 10(5) cells). In contrast to the result when using a stepwise dose increase of IL-2 either without or with a fixed production of IL-12 (4-5 ng/5 x 10(5) cells/24 hours, insufficient for tumor rejection by itself), rejection of the tumor was achieved in 75% of the mice when the IL-12 secretion was combined with high and transient IL-2 production (42 ng/5 x 10(5) cells/24 hours) using additional adenoviral vector transduction (100 multiplicities of infection). An abundant infiltration of both CD4+ (47.4/mm2) and CD8+ (85.6/mm2) T cells was a characteristic finding in the dual gene-transfected LLC tumors. Importantly, consistent with the rejection of rechallenged parental cells, tumor-specific cytotoxic T lymphocytes were induced only from the splenocytes of mice inoculated with the dual gene-transduced LLC cells, suggesting the existence of protective antitumor memory. In addition, only vaccination of dual gene-transduced LLC cells inhibited the growth of pre-established LLC tumors. These results indicate that generation of a pivotal antitumor response likely depends on the synergistic combination and concentration of IL-2 and IL-12 in the local milieu by which tumor-specific immune memory is established.
Tanaka
M
M
Department of Respiratory Oncology and Molecular Medicine, Institute of Development, Aging, and Cancer, Tohoku University, Sendai, Japan.
Saijo
Y
Y
Sato
G
G
Suzuki
T
T
Tazawa
R
R
Satoh
K
K
Nukiwa
T
T
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D018827:Carcinoma, Lewis Lung / Q000628:therapy*; D002455:Cell Division; D004305:Dose-Response Relationship, Drug; D015316:Genetic Therapy / Q000379:methods*; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000235:genetics*; D007376:Interleukin-2 / Q000235:genetics*; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D008546:Melanoma, Experimental / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D012190:Retroviridae / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism; D013997:Time Factors; D014407:Tumor Cells, Cultured
D007376:Interleukin-2; D018664:Interleukin-12; D007371:Interferon-gamma