High Stromal TGFBI in Lung Cancer and Intratumoral CD8-Positive T Cells were Associated with Poor Prognosis and Therapeutic Resistance to Immune Checkpoint Inhibitors
High Stromal TGFBI in Lung Cancer and Intratumoral CD8-Positive T Cells were Associated with Poor Prognosis and Therapeutic Resistance to Immune Checkpoint Inhibitors
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DOI：
10.1245/s10434-019-07878-8
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发表时间：
2019-09-30
影响因子：
3.7
通讯作者：
Shirabe, Ken
中科院分区：
文献类型：
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作者：
Nakazawa, Nobuhiro;Yokobori, Takehiko;Shirabe, Ken
我们研究了临床肺癌患者中转化生长因子β诱导蛋白（TGFBI）和肿瘤内免疫细胞（包括CD 8和叉头盒蛋白P3（Foxp 3）阳性T细胞）的表达是否可以预测对纳武利尤单抗的治疗反应。方法33例患者接受纳武利尤单抗治疗。对TGFBI、PD-L1、CD 8、Foxp 3和波形蛋白表达进行免疫组织化学分析。采用酶联免疫吸附试验（ELISA）测定血清中TGFBI和转化生长因子-β 1（TGF-β 1）的浓度。结果肿瘤TGFBI与nivolumab的预后和治疗反应无关，但肿瘤间质TGFBI和肿瘤内CD 8阳性T细胞与预后和治疗反应相关。因此，我们评估了癌间质TGFBI和肿瘤内CD 8阳性T细胞。高TGFBI表达组的临床反应比低TGFBI表达组差（p < 0.0001）。在高CD 8表达组中给予纳武单抗的次数显著高于低CD 8表达组（p = 0.0046）。高CD 8表达组的临床反应优于低CD 8表达组（p = 0.0013）。有趣的是，高TGFBI/低CD 8表达组中的所有患者都有疾病进展（PD）。相比之下，根据实体瘤疗效评价标准（RECIST 1.1），低TGFBI/高CD 8表达组的所有患者均为PR + SD（部分缓解+疾病稳定）。结论间质TGFBI和瘤内CD 8阳性T细胞的双重评估可能是纳武利尤单抗的有用预测标志物。
Background We investigated whether the expression of transforming growth factor-beta-induced protein (TGFBI) and intratumoral immune cells including CD8- and Forkhead box protein P3 (Foxp3)-positive T cells in clinical lung cancer patients could predict the therapeutic response to nivolumab. Methods Thirty-three patients who were treated with nivolumab were enrolled in this study. Immunohistochemical analyses of TGFBI, PD-L1, CD8, Foxp3, and vimentin expression were conducted. Serum concentrations of TGFBI and transforming growth factor-beta1 (TGF-beta 1) were determined by enzyme-linked immunosorbent assay (ELISA). Results Cancer TGFBI was not associated with prognosis and therapeutic response to nivolumab, but cancer stromal TGFBI and intratumoral CD8-positive T cells were associated with them. Therefore, we evaluated cancer stromal TGFBI and intratumoral CD8-positive T cells. The high-TGFBI-expression group had poorer clinical responses than did the low-TGFBI-expression group (p < 0.0001). The number of times nivolumab was administered in the high-CD8-expression group was significantly higher than that in the low-CD8-expression group (p = 0.0046). The high-CD8-expression group had better clinical responses than did the low-CD8-expression group (p = 0.0013). Interestingly, all patients in the high-TGFBI/low-CD8-expression group had progressive disease (PD). In contrast, all patients in the low-TGFBI/high-CD8-expression group had PR + SD (partial response + stable disease) by the Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Conclusions The dual evaluation of stromal TGFBI and intratumoral CD8-positive T cells could be a useful predictive marker for nivolumab.