Zhao Mingxia, Guo Wenjie, Wu Yuanyuan, Yang Chenxi, Zhong Liang, Deng Guoliang, Zhu Yuyu, Liu Wen, Gu Yanhong, Lu Yin, Kong Lingdong, Meng Xiangbao, Xu Qiang, Sun Yang
State Key Laboratory of Pharmaceutical Biotechnology, Deparment of Biotechnology and Pharmaceutical Sciences, School of Life Sciences, Nanjing University, Nanjing 210023, China.
Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
Acta Pharm Sin B. 2019 Mar;9(2):304-315. doi: 10.1016/j.apsb.2018.08.009. Epub 2018 Sep 5.
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 and . However, whether SHP099-mediated SHP2 inhibition retards tumor growth 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 CD8IFN- T cells and the upregulation of cytotoxic T-cell related genes including , 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.
酪氨酸磷酸酶SHP2在癌症免疫治疗中是一个有前景的药物靶点，因为它在促进肿瘤生长和使T细胞失活这两方面都发挥着双向作用。已知其变构抑制剂SHP099在体外和体内均能抑制癌细胞生长。然而，SHP099介导的对SHP2的抑制是否会延缓肿瘤生长以及抗肿瘤免疫仍不清楚。为了解决这个问题，在小鼠中建立了CT-26结肠癌异种移植模型，因为这种细胞系对SHP099不敏感。因此，SHP099对免疫缺陷的裸鼠体内CT-26肿瘤生长影响极小，但在免疫系统完整的荷CT-26肿瘤小鼠中显著降低了肿瘤负荷。SHP099增强了抗肿瘤免疫，表现为CD8+IFN-γ+ T细胞比例升高以及包括颗粒酶B和穿孔素在内的细胞毒性T细胞相关基因上调，从而降低了肿瘤负荷。此外，由于抗肿瘤反应增强，SHP2缺陷型T细胞的小鼠体内肿瘤生长明显减缓。最后，在两种结肠癌异种移植模型中，SHP099与抗PD-1抗体联合使用在控制肿瘤生长方面显示出比单一疗法更高的治疗效果，表明这些药物相互补充。我们的研究表明，SHP2抑制剂SHP099是癌症免疫治疗中一个有前景的候选药物。
