Down-regulation of IL-10 enhances the efficacy of locoregional immunotherapy using OK-432 against malignant effusion.
To determine the significance of interleukin (IL)-10 in antitumor immune response, the effect of the down-regulation of tumor-derived IL-10 on locoregional immunotherapy was investigated. C3H/HeN mice were intraperitoneally (i.p.) inoculated with IL-10-producing murine breast cancer cell line, FM3A, and treated with locoregional administration of OK-432 with or without anti-IL-10 monoclonal antibody (mAb). Anti-IL-10 mAb did not affect the in vitro growth of FM3A cells. Administration of OK-432 plus anti-IL-10 mAb remarkably delayed the retention of malignant ascites and prolonged the survival of mice compared with the administration of OK-432 alone. Spleen cells which were collected from mice treated with OK-432 plus anti-IL-10 mAb and further stimulated in vitro with inactivated FM3A cells exhibited significantly higher cytotoxicity against FM3A cells than those from mice treated with OK-432 alone or from the control mice. The expression of major histocompatibility complex (MHC) class II molecules on spleen cells was up-regulated in vitro by the addition of OK-432 and anti-IL-10 mAb. Using semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR), cytokine mRNA levels of peritoneal exudate cells (PEC) and spleen cells were assessed on day 7 (before treatment) and day 14 (after treatment). In PEC, increased expression of IL-2 was observed with the administration of OK-432 plus anti-IL-10 mAb. In spleen cells, the expression of IL-2, IL-12 and IFN-gamma were strongly induced, and IL-4 expression was reduced by the administration of OK-432 plus anti-IL-10 mAb. It is suggested that down-regulation of tumor-derived IL-10 induces the up-regulation of the T helper type (Th) 1 population, resulting in an enhancement of the efficacy of locoregional immunotherapy with OK-432.
Hihara
J
J
Department of Surgical Oncology, Hiroshima University, Japan.
Yamaguchi
Y
Y
Minami
K
K
Noma
K
K
Toge
T
T
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001201:Ascites / Q000188:drug therapy*; D016207:Cytokines / Q000235:genetics; D000949:Histocompatibility Antigens Class II / Q000032:analysis; D016753:Interleukin-10 / Q000037:antagonists & inhibitors*; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy*; D051379:Mice; D008809:Mice, Inbred C3H; D010844:Picibanil / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000032:analysis
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D016207:Cytokines; D000949:Histocompatibility Antigens Class II; D012333:RNA, Messenger; D016753:Interleukin-10; D010844:Picibanil