Shi Shengbin, Rao Quan, Zhang Chuangnian, Zhang Xiuyuan, Qin Yibo, Niu Zuoxing
Institute of Biomedical Engineering, Chinese Academy of Medical Sciences, Peking Union Medical College, Tianjin Key Laboratory of Biomaterial Research, Tianjin 300192, China; Department of Medical Oncology, Shandong Cancer Hospital and Institute, Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China.
Third Central Clinical College, Tianjin Medical University, Tianjin 300170, China.
Transl Oncol. 2018 Apr;11(2):250-258. doi: 10.1016/j.tranon.2018.01.001. Epub 2018 Jan 28.
Advanced hepatocellular carcinoma (HCC) has limited therapeutic options. Immunotherapy is a promising treatment, while sorafenib is a first-line drug-based treatment for advanced HCC. However, the efficacy of sorafenib and immunotherapy in combination, have not been clearly evaluated. Sorafenib treatment has been shown to promote immunosuppression by increasing hypoxia in orthotopic HCC models. Here, we found that sorafenib treatment in mice with orthotopic HCC increased the expression of inhibitor programmed death-ligand 1 (PD-L1) and T-regulatory cells in tumor tissues. We pulsed dendritic cells with exosomes derived from tumor cells (DC-TEX) and found that the number of T-regulatory cells decreased and the number of CD8+T cells increased. However, combining DC-TEX and sorafenib did not prolong survival in these mice. Moreover, we found that the number of PD-1+CD8+T cells significantly increased after DC-TEX treatment. Therefore, we next added PD-1 antibody (PD-1 Ab) to the treatment regimen to block the PD-1/PD-L1 pathway, and found that the exhausted CD8+T cells were restored, without affecting the number of T-regulatory cells. Thus, our data suggest that the combination of DC-TEX and PD-1 Ab enhanced the efficacy of sorafenib, but treatment with either DC-TEX or PD-1 Ab alone, did not.
晚期肝细胞癌（HCC）的治疗选择有限。免疫疗法是一种有前景的治疗方法，而索拉非尼是晚期HCC基于药物的一线治疗药物。然而，索拉非尼与免疫疗法联合使用的疗效尚未得到明确评估。在原位HCC模型中，索拉非尼治疗已被证明通过增加缺氧来促进免疫抑制。在此，我们发现原位HCC小鼠接受索拉非尼治疗后，肿瘤组织中抑制性程序性死亡配体1（PD-L1）和调节性T细胞的表达增加。我们用源自肿瘤细胞的外泌体刺激树突状细胞（DC-TEX），发现调节性T细胞数量减少，CD8+T细胞数量增加。然而，DC-TEX与索拉非尼联合使用并未延长这些小鼠的生存期。此外，我们发现DC-TEX治疗后PD-1+CD8+T细胞数量显著增加。因此，我们接下来在治疗方案中添加PD-1抗体（PD-1 Ab）以阻断PD-1/PD-L1通路，发现耗竭的CD8+T细胞得以恢复，且不影响调节性T细胞数量。因此，我们的数据表明，DC-TEX与PD- Ab联合使用可增强索拉非尼的疗效，但单独使用DC-TEX或PD-1 Ab治疗则不然。
