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Inhibition of the B7-H3 immune checkpoint limits tumor growth by enhancing cytotoxic lymphocyte function.
Cell Research ( IF 28.1 ) Pub Date : 2017-07-07 , DOI: 10.1038/cr.2017.90
Young-Hee Lee 1 , Natalia Martin-Orozco 1, 2 , Peilin Zheng 3, 4, 5 , Jing Li 6 , Peng Zhang 7 , Haidong Tan 8 , Hyun Jung Park 9 , Mira Jeong 10 , Seon Hee Chang 1 , Byung-Seok Kim 1 , Wei Xiong 4, 5 , Wenjuan Zang 6 , Li Guo 11 , Yang Liu 7 , Zhong-Jun Dong 6 , Willem W Overwijk 12 , Patrick Hwu 12 , Qing Yi 13, 14 , Larry Kwak 13, 15 , Zhiying Yang 8 , Tak W Mak 16 , Wei Li 9 , Laszlo G Radvanyi 2, 12 , Ling Ni 6 , Dongfang Liu 3, 4 , Chen Dong 6
Affiliation  

The interaction between tumor and the immune system is still poorly understood. Significant clinical responses have been achieved in cancer patients treated with antibodies against the CTLA4 and PD-1/PD-L1 checkpoints; however, only a small portion of patients responded to the therapies, indicating a need to explore additional co-inhibitory molecules for cancer treatment. B7-H3, a member of the B7 superfamily, was previously shown by us to inhibit T-cell activation and autoimmunity. In this study, we have analyzed the function of B7-H3 in tumor immunity. Expression of B7-H3 was found in multiple tumor lines, tumor-infiltrating dendritic cells, and macrophages. B7-H3-deficient mice or mice treated with an antagonistic antibody to B7-H3 showed reduced growth of multiple tumors, which depended on NK and CD8+ T cells. With a putative receptor expressed by cytotoxic lymphocytes, B7-H3 inhibited their activation, and its deficiency resulted in increased cytotoxic lymphocyte function in tumor-bearing mice. Combining blockades of B7-H3 and PD-1 resulted in further enhanced therapeutic control of late-stage tumors. Taken together, our results indicate that the B7-H3 checkpoint may serve as a novel target for immunotherapy against cancer.

中文翻译:

B7-H3免疫检查点的抑制作用通过增强细胞毒性淋巴细胞功能来限制肿瘤的生长。

肿瘤与免疫系统之间的相互作用仍然知之甚少。在用抗CTLA4和PD-1 / PD-L1检查点抗体治疗的癌症患者中,已经取得了重要的临床反应。然而,只有一小部分患者对疗法有反应,这表明需要探索更多的共抑制分子来治疗癌症。B7-H3是B7超家族的成员,我们之前曾证明它可以抑制T细胞活化和自身免疫。在这项研究中,我们分析了B7-H3在肿瘤免疫中的功能。在多个肿瘤系,肿瘤浸润性树突状细胞和巨噬细胞中发现了B7-H3的表达。缺乏B7-H3的小鼠或接受B7-H3拮抗抗体治疗的小鼠表现出多种肿瘤的生长减少,这取决于NK和CD8 + T细胞。通过细胞毒性淋巴细胞表达的推定受体,B7-H3抑制了它们的活化,其缺乏导致荷瘤小鼠细胞毒性淋巴细胞功能增强。B7-H3和PD-1的联合封锁导致晚期肿瘤的治疗控制得到进一步增强。两者合计,我们的结果表明,B7-H3检查点可以作为针对癌症的免疫疗法的新靶标。
更新日期:2017-08-07
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