Indoleamine 2,3-dioxygenase promotes peritoneal metastasis of ovarian cancer by inducing an immunosuppressive environment.
Indoleamine 2,3-dioxygenase promotes peritoneal metastasis of ovarian cancer by inducing an immunosuppressive environment.
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DOI：
10.1111/cas.12445
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发表时间：
2014-08
期刊：
影响因子：
5.7
通讯作者：
Ino K
中科院分区：
文献类型：
--
作者：
Tanizaki Y;Kobayashi A;Toujima S;Shiro M;Mizoguchi M;Mabuchi Y;Yagi S;Minami S;Takikawa O;Ino K
吲哚胺2，3-双加氧酶（Indoleamine 2，3-dioxygenase，IDO）是一种具有免疫调节功能的色氨酸代谢酶。我们先前的研究表明，肿瘤IDO过表达参与了人类卵巢癌的疾病进展和患者生存率受损，尽管其机制尚不清楚。本研究的目的是阐明IDO在卵巢癌腹膜播散过程中的作用。将吲哚胺2，3-双加氧酶cDNA转染到小鼠卵巢癌细胞系OV 2944-HM-1中，建立IDO过表达细胞（HM-1-IDO）的稳定克隆。然后将HM-1-IDO或对照载体转染的细胞（HM-1-mock）腹膜内移植到同系免疫活性小鼠中。与HM-1-模拟移植（对照）小鼠相比，HM-1-IDO移植小鼠显示出显著缩短的存活。在移植后第11和14天，HM-1-IDO移植小鼠的腹膜播散的肿瘤重量和腹水量与对照小鼠相比显著增加。这种肿瘤进展效应与肿瘤内CD 8 + T细胞和自然杀伤细胞数量显著减少以及腹水中转化生长因子-β和白细胞介素-10水平升高一致。最后，用IDO抑制剂1-甲基-色氨酸治疗显著抑制了肿瘤播散和腹水，同时降低了转化生长因子-β分泌。这些发现表明，肿瘤来源的IDO通过抑制肿瘤浸润效应T细胞和自然杀伤细胞募集以及腹水中免疫抑制细胞因子的相互增强，在腹膜腔内产生免疫耐受环境，促进卵巢癌的腹膜扩散。因此，IDO可能是卵巢癌治疗策略的一个有前途的分子靶点。
Indoleamine 2,3-dioxygenase (IDO) is a tryptophan-catabolizing enzyme that has immunoregulatory functions. Our prior study showed that tumoral IDO overexpression is involved in disease progression and impaired patient survival in human ovarian cancer, although its mechanism remains unclear. The purpose of the present study is to clarify the role of IDO during the process of peritoneal dissemination of ovarian cancer. Indoleamine 2,3-dioxygenase cDNA was transfected into the murine ovarian carcinoma cell line OV2944-HM-1, establishing stable clones of IDO-overexpressing cells (HM-1-IDO). Then HM-1-IDO or control vector-transfected cells (HM-1-mock) were i.p. transplanted into syngeneic immunocompetent mice. The HM-1-IDO-transplanted mice showed significantly shortened survival compared with HM-1-mock-transplanted (control) mice. On days 11 and 14 following transplantation, the tumor weight of peritoneal dissemination and ascites volume were significantly increased in HM-1-IDO-transplanted mice compared with those of control mice. This tumor-progressive effect was coincident with significantly reduced numbers of CD8+ T cells and natural killer cells within tumors as well as increased levels of transforming growth factor-β and interleukin-10 in ascites. Finally, treatment with the IDO inhibitor 1-methyl-tryptophan significantly suppressed tumor dissemination and ascites with reduced transforming growth factor-β secretion. These findings showed that tumor-derived IDO promotes the peritoneal dissemination of ovarian cancer through suppression of tumor-infiltrating effector T cell and natural killer cell recruitment and reciprocal enhancement of immunosuppressive cytokines in ascites, creating an immunotolerogenic environment within the peritoneal cavity. Therefore, IDO may be a promising molecular target for the therapeutic strategy of ovarian cancer.
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DOI：
10.1158/1078-0432.ccr-12-2130
发表时间：
2012-11-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Wainwright DA;Balyasnikova IV;Chang AL;Ahmed AU;Moon KS;Auffinger B;Tobias AL;Han Y;Lesniak MS
通讯作者：
Lesniak MS
影响因子：
8.8
作者：
Ino, K;Yoshida, N;Kajiyama, H;Shibata, K;Yamamoto, E;Kidokoro, K;Takahashi, N;Terauchi, M;Nawa, A;Nomura, S;Nagasaka, T;Takikawa, O;Kikkawa, F
通讯作者：
Kikkawa, F
影响因子：
28.2
作者：
Smith C;Chang MY;Parker KH;Beury DW;DuHadaway JB;Flick HE;Boulden J;Sutanto-Ward E;Soler AP;Laury-Kleintop LD;Mandik-Nayak L;Metz R;Ostrand-Rosenberg S;Prendergast GC;Muller AJ
通讯作者：
Muller AJ
影响因子：
5.1
作者：
Liu, Chan-zhen;Zhang, Li;Cui, Heng
通讯作者：
Cui, Heng
影响因子：
2.9
作者：
Toyoshima, Masafumi;Tanaka, Yoshinori;Yaegashi, Nobuo
通讯作者：
Yaegashi, Nobuo