Kobayashi Aya, Tanizaki Yuko, Kimura Akihiko, Ishida Yuko, Nosaka Mizuho, Toujima Saori, Kuninaka Yumi, Minami Sawako, Ino Kazuhiko, Kondo Toshikazu
Department of Obstetrics and Gynecology, Wakayama Medical University, Wakayama, Japan; Department of Forensic Medicine, Wakayama Medical University, Wakayama, Japan.
Department of Forensic Medicine, Wakayama Medical University, Wakayama, Japan.
Eur J Pharmacol. 2015 Nov 5;766:63-75. doi: 10.1016/j.ejphar.2015.09.039. Epub 2015 Sep 26.
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.
卵巢癌是女性生殖系统恶性肿瘤中导致癌症死亡的主要原因，因此需要开发新的治疗方法。肿瘤细胞的免疫逃逸和耐受性的获得是癌症生长和进展的关键。肿瘤中免疫调节酶吲哚胺2,3-双加氧酶（IDO）的过表达是宿主免疫耐受的关键。Janus激酶-信号转导子和转录激活子（JAK-STAT）通路参与多种肿瘤生物学过程。因此，我们研究了AG490（一种JAK2抑制剂）抑制STAT1对小鼠卵巢癌进展的影响。体外研究中，IFN-γ处理可通过激活STAT1上调OV2944-HM-1细胞中Ido mRNA的表达，而AG490处理可通过抑制STAT1磷酸化显著抑制这种作用。在体内模型中，将OV2944-HM-1细胞腹腔内/皮下接种到同基因免疫活性雌性小鼠体内。与对照组相比，AG490处理显著抑制了皮下肿瘤的生长。同样，在腹腔内接种HM-1细胞的小鼠中，相同处理显著提高了生存率，减少了腹腔内肿瘤的数量。实际上，在AG490处理的小鼠中，肿瘤内IDO表达随着STAT1激活的减少而显著抑制。此外，在AG490处理的小鼠肿瘤微环境中，抗肿瘤白细胞如CD8(+) T细胞、M1巨噬细胞和NK细胞的积累明显增加，而调节性T细胞则相应减少。此外，在AG490处理的小鼠中，肿瘤内抗肿瘤细胞因子如IL-1α、IL-1β和IL-12的表达显著增强。总之，JAK/STAT信号通路可能是卵巢癌免疫治疗的良好分子靶点。
