Ovarian cancer is the major cause of
cancer death among female genital
malignancies, and requires developing novel therapeutic measures. Immune escape and acquisition of tolerance by
tumor cells are essential for
cancer growth and progression. An immunoregulatory
enzyme indoleamine 2,3-dioxygenase (IDO) overexpression in
tumors is essential for host immune tolerance. Janus-activated
kinase-signal transducer and activator of transcription (JAK-STAT) pathway is involved in various kinds of
tumor biology. Thus, we examined the effects of STAT1 inhibition by
AG490 (a JAK2 inhibitor) on
ovarian cancer progression in mice. In vitro study, IFN-γ treatment up-regulated Ido
mRNA expression with STAT1 activation in OV2944-HM-1 cells, whereas
AG490 treatment significantly inhibited this effect with the suppression of STAT1 phosphorylation. In vivo model, OV2944-HM-1 cells were intraperitoneally/subcutaneously transplanted into syngeneic immunocompetent female mice.
AG490 treatment significantly suppressed subcutaneous
tumor growth, compared with control. Consistently, in mice intraperitoneally inoculated HM-1 cells, the same treatment significantly improved survival rate with the reduced number of intraperitoneal
tumors. Actually, intratumoral IDO expression was significantly suppressed with the reduction of STAT1 activation in AG490-treated mice. Moreover, in tumor microenvironment of mice treated with
AG490, the accumulation of anti-
tumor leukocytes such as CD8(+) T-cells, M1 macrophages, and NK cells was apparently exaggerated with the reciprocal reduction of regulatory T cells. Furthermore, intratumoral expression of anti-
tumor cytokines such as IL-1α, IL-1β and
IL-12 expression was significantly enhanced in mice treated with
AG490. Collectively, JAK/STAT signal pathways may be good molecular target for
immunotherapy of
ovarian cancer.