PD-1+ and Foxp3+ T cell reduction correlates with survival of HCC patients after sorafenib therapy
PD-1+ and Foxp3+ T cell reduction correlates with survival of HCC patients after sorafenib therapy
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DOI：
10.1172/jci.insight.86182
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发表时间：
2016-07-21
期刊：
影响因子：
8
通讯作者：
Thanavala, Yasmin
中科院分区：
文献类型：
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作者：
Kalathil, Suresh Gopi;Lugade, Amit Anand;Thanavala, Yasmin
背景资料。索拉非尼是一种口服抗血管生成剂，用于治疗晚期肝细胞癌。基于临床前和人体研究，我们假设，除了其抗血管生成的特性外，索拉非尼还可以有益地减少肝细胞癌患者免疫抑制网络的范围。为了验证这一假设，我们检验了晚期肝癌患者免疫抑制负荷的变化是否与临床结果相关。方法：在索拉非尼治疗前后，19名晚期肝癌患者的血液样本，PD-1(+)T细胞、Tregs和髓系衍生抑制细胞(MDSC)的频率被多参数FACS定量。结果索拉非尼治疗后，CD4(+)PD-1(+)T细胞和CD8(+)PD-1(+)T细胞绝对数的减少对总存活率(OS)有显著影响。Foxp3(+)Tregs的频率和绝对数量也显著减少，在Foxp3(+)Tregs数量减少更多的患者中，OS有统计学上的显著改善。经索拉非尼治疗后，CD4(+)CD127(+)PD-1-T效应细胞与CD4(+)Foxp3(+)PD-1(+)Tregs的比值明显升高。结论本研究首次证实了索拉非尼对PD-1(+)T细胞和Tregs的免疫调节作用及其与生存期的关系。这些表型可以作为预测生物标志物，以确定谁可能受益于索拉非尼治疗的肝癌患者。
BACKGROUND. Sorafenib is an oral antiangiogenic agent administered in advanced-stage hepatocellular carcinoma (HCC). Based on preclinical and human studies, we hypothesized that, in addition to its antiangiogenic properties, sorafenib may beneficially reduce the extent of the immunosuppressive network in HCC patients. To test this hypothesis, we examined whether alterations in the immunosuppressive burden of advanced-stage HCC patients correlated with clinical outcome.METHODS. In before and after sorafenib treatment, blood samples collected from 19 patients with advanced HCC, the frequency of PD-1(+) T cells, Tregs, and myeloid derived suppressor cells (MDSC) were quantified by multiparameter FACS. Cytokine levels in plasma were determined by ELISA.RESULTS. Overall survival (OS) was significantly impacted by the reduction in the absolute number of both CD4(+)PD-1(+)T cells and CD8(+)PD-1(+)T cells following sorafenib treatment. Significant decreases in the frequency and absolute number of Foxp3(+)Tregs were also observed, and a statistically significant improvement in OS was noted in patients exhibiting a greater decrease in the number of Foxp3(+)Tregs. The ratio of CD4(+)CD127(+)PD-1-T effector cells to CD4(+)Foxp3(+)PD-1(+) Tregs was significantly increased following treatment with sorafenib. Increased frequency of CD4(+)CD127(+)T effector cells in the posttreatment samples significantly correlated with OS.CONCLUSION. This study is the first to our knowledge to demonstrate the potent immunomodulatory effects of sorafenib therapy on PD-1(+) T cells and Tregs and the ensuing correlation with survival. These phenotypes could serve as predictive biomarkers to identify HCC patients who are likely to benefit from sorafenib treatment.