Host b7x promotes pulmonary metastasis of breast cancer.
Host b7x promotes pulmonary metastasis of breast cancer.
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DOI：
10.4049/jimmunol.1202439
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发表时间：
2013-04-01
期刊：
影响因子：
--
通讯作者：
Zang X
中科院分区：
文献类型：
--
作者：
Abadi YM;Jeon H;Ohaegbulam KC;Scandiuzzi L;Ghosh K;Hofmeyer KA;Lee JS;Ray A;Gravekamp C;Zang X
B7x （B7- h4或B7S1）是T细胞共刺激B7家族的抑制性成员。它在健康的外周组织（如肺上皮）中表达水平较低，但在多种人类癌症中过度表达，并与包括转移在内的临床负相关。然而，B7x在癌症背景下的功能，无论是在癌细胞上表达还是在周围的“宿主”组织上表达，尚未在体内阐明。我们利用4T1转移性乳腺癌模型和B7x敲除（B7x−/−）小鼠来研究宿主组织表达的B7x对癌症的影响。我们发现4T1细胞在体外和体内均为B7x阴性，B7x - / -小鼠的肺4T1肿瘤结节明显少于野生型小鼠。此外，B7x - / -小鼠对肿瘤再攻击表现出显著提高的存活率和记忆反应。机制研究表明，B7x的存在与一般和肿瘤特异性T细胞细胞因子反应的降低以及免疫抑制细胞（包括肿瘤相关中性粒细胞（TANs）、巨噬细胞和调节性T细胞）进入肿瘤肺的浸润增加有关。重要的是，TANs强烈结合B7x蛋白并抑制CD4和CD8 T细胞的增殖。这些结果表明，宿主B7x可能通过与先天免疫系统和适应性免疫系统的相互作用，使转移的癌细胞逃脱局部抗肿瘤免疫反应。因此，靶向B7x通路有望提高转移性癌症的免疫治疗效果。
B7x (B7-H4 or B7S1) is an inhibitory member of the B7 family of T cell costimulation. It is expressed in low levels in healthy peripheral tissues such as the lung epithelium, but over-expressed in a variety of human cancers with negative clinical associations including metastasis. However, the function of B7x in the cancer context, whether expressed on cancer cells or on surrounding “host” tissues, has not been elucidated in vivo. We utilized the 4T1 metastatic breast cancer model and B7x knockout (B7x−/−) mice to investigate the effect of host tissue-expressed B7x on cancer. We found that 4T1 cells were B7x negative in vitro and in vivo and B7x−/− mice had significantly fewer lung 4T1 tumor nodules than wildtype mice. Furthermore, B7x−/− mice showed significantly enhanced survival and a memory response to tumor rechallenge. Mechanistic studies revealed that the presence of B7x correlated with reduced general and tumor-specific T cell cytokine responses, as well as with an increased infiltration of immunosuppressive cells, including tumor associated neutrophils (TANs), macrophages, and regulatory T cells into tumor-bearing lungs. Importantly, the TANs strongly bound B7x protein and inhibited proliferation of both CD4 and CD8 T cells. These results suggest that host B7x may enable metastasizing cancer cells to escape local anti-tumor immune responses through interactions with the innate as well as the adaptive immune systems. Targeting the B7x pathway thus holds much promise for improving the efficacy of immunotherapy for metastatic cancer.
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影响因子：
3.7
作者：
Fridlender ZG;Sun J;Mishalian I;Singhal S;Cheng G;Kapoor V;Horng W;Fridlender G;Bayuh R;Worthen GS;Albelda SM
通讯作者：
Albelda SM
影响因子：
20.3
作者：
Movahedi, Kiavash;Guilliams, Martin;Van Ginderachter, Jo A.
通讯作者：
Van Ginderachter, Jo A.
影响因子：
5.8
作者：
Chen, Lu-jun;Sun, Jing;Zhang, Xue-guang
通讯作者：
Zhang, Xue-guang
影响因子：
3.6
作者：
duPre', Sally A.;Hunter, Kenneth W., Jr.
通讯作者：
Hunter, Kenneth W., Jr.
DOI：
10.1084/jem.20100587
发表时间：
2010-10-25
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Corzo CA;Condamine T;Lu L;Cotter MJ;Youn JI;Cheng P;Cho HI;Celis E;Quiceno DG;Padhya T;McCaffrey TV;McCaffrey JC;Gabrilovich DI
通讯作者：
Gabrilovich DI