SHP2 inhibition triggers anti-tumor immunity and synergizes with PD-1 blockade
SHP2 inhibition triggers anti-tumor immunity and synergizes with PD-1 blockade
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SHP2 抑制可触发抗肿瘤免疫并与 PD-1 阻断产生协同作用
DOI：
10.1016/j.apsb.2018.08.009
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发表时间：
2019-03-01
影响因子：
14.5
通讯作者：
Sun, Yang
中科院分区：
文献类型：
--
作者：
Zhao, Mingxia;Guo, Wenjie;Sun, Yang
酪氨酸磷酸酶SHP 2由于其在肿瘤生长促进和T细胞失活中的双向作用而在癌症免疫治疗中是有希望的药物靶点。已知其变构抑制剂SHP 099在体外和体内均抑制癌细胞生长。然而，SHP 099介导的SHP 2抑制是否通过抗肿瘤免疫在体内延缓肿瘤生长仍然是难以捉摸的。为了解决这一问题，在小鼠中建立了CT-26结肠癌异种移植模型，因为该细胞系对SHP 099不敏感。因此，SHP 099对免疫缺陷裸鼠中CT-26肿瘤生长的影响极小，但显著降低了免疫系统完整的CT-26荷瘤小鼠的肿瘤负荷。SHP 099增强了抗肿瘤免疫，表现为CD 8（+）IFN（-）γ（+）T细胞比例升高和细胞毒性T细胞相关基因（包括颗粒酶B和穿孔素）上调，从而降低了肿瘤负荷。此外，由于增强的抗肿瘤反应，具有SHP 2缺陷T细胞的小鼠中的肿瘤生长显著减慢。最后，在两种结肠癌异种移植模型中，SHP 099和抗PD-1抗体联合治疗在控制肿瘤生长方面显示出比单药治疗更高的疗效，表明这些药物相互补充。我们的研究表明，SHP 2抑制剂SHP 099是一种很有前途的癌症免疫治疗候选药物。(C)2019中国药学会、中国医学科学院药物研究所。制作和主办：Elsevier B. V.
Tyrosine phosphatase SHP2 is a promising drug target in cancer immunotherapy due to its bidirectional role in both tumor growth promotion and T-cell inactivation. Its allosteric inhibitor SHP099 is known to inhibit cancer cell growth both in vitro and in vivo. However, whether SHP099-mediated SHP2 inhibition retards tumor growth in vivo via anti-tumor immunity remains elusive. To address this, a CT-26 colon cancer xenograft model was established in mice since this cell line is insensitive to SHP099. Consequently, SHP099 minimally affected CT-26 tumor growth in immuno-deficient nude mice, but significantly decreased the tumor burden in CT-26 tumor-bearing mice with intact immune system. SHP099 augmented anti-tumor immunity, as shown by the elevated proportion of CD8(+)IFN(-)gamma(+) T cells and the upregulation of cytotoxic T-cell related genes including Granzyme B andPerforin, which decreased the tumor load. In addition, tumor growth in mice with SHP2-deficient T-cells was markedly slowed down because of enhanced anti-tumor responses. Finally, the combination of SHP099 and anti-PD-1 antibody showed a higher therapeutic efficacy than either monotherapy in controlling tumor growth in two colon cancer xenograft models, indicating that these agents complement each other. Our study suggests that SHP2 inhibitor SHP099 is a promising candidate drug for cancer immunotherapy. (C) 2019 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.