Immunomodulator OM 163-induced reversal of tumor-mediated immunosuppression and downregulation of TGF-beta 1 in vivo.
Although PROb colonic tumor cells are immunosuppressive, the immunomodulator OM 163 induced the disappearance of macroscopic peritoneal nodules in 50% of rats bearing a peritoneal carcinomatosis (p.c.) induced by PROb cells. When the p.c. developed, the number of T lymphocytes was low and the expression of interferon (IFN)-gamma mRNA in tumor nodules decreased very rapidly. The TGF-beta 1 secreted by PROb cells could be responsible for the immunosuppression, because the PROb cell supernatant inhibited IFN-gamma production and T lymphocyte proliferation. When the rats were treated with OM 163, an infiltration of T lymphocytes was observed in tumor nodules, as well as a high expression of the IFN-gamma mRNA. The antitumor efficiency of the immunomodulator OM 163 could be explained in part by a direct effect of OM 163 on T lymphocytes, because in vitro it stimulated the proliferation and the secretion of IFN-gamma of T lymphocytes. OM 163 could also act at the TGF-beta 1 level. Although OM 163 alone or in combination with IFN-gamma did not modify the TGF-beta 1 secretion by PROb cells in vitro, the expression of the TGF-beta 1 mRNA and the TGF-beta 1 protein content was decreased in vivo in treated tumor nodules.
Lagadec
P
P
Cancer Immunotherapy Research Laboratory, Ecole Pratique des Hautes Etudes, Faculty of Medicine, Dijon, France.
Reveneau
S
S
Lejeune
P
P
Pinard
D
D
Borman
T
T
Bauer
J
J
Jeannin
J F
JF
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects*; D004926:Escherichia coli; D015870:Gene Expression / Q000187:drug effects; D007165:Immunosuppression Therapy; D008214:Lymphocytes / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D000276:Adjuvants, Immunologic; D000970:Antineoplastic Agents; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta