The tumor inflammation signature (TIS) is associated with anti-PD-1 treatment benefit in the CERTIM pan-cancer cohort
The tumor inflammation signature (TIS) is associated with anti-PD-1 treatment benefit in the CERTIM pan-cancer cohort
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DOI：
10.1186/s12967-019-2100-3
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发表时间：
2019-11-04
影响因子：
7.4
通讯作者：
Leroy, Karen
中科院分区：
文献类型：
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作者：
Damotte, Diane;Warren, Sarah;Leroy, Karen
背景18基因肿瘤炎症标记（TIS）是一种临床研究测定，丰富了免疫检查点阻断的临床益处。我们评估了其预测在常规临床护理中接受PD-1检查点抑制剂治疗的癌症患者的免疫治疗临床获益的能力。方法CERTIM队列是一个前瞻性队列，包括在科钦大学医院接受免疫检查点抑制剂治疗的患者。从58个福尔马林固定的石蜡包埋的肿瘤块（包括38个肺癌、5个黑色素瘤、10个肾癌、4个尿路上皮癌和1个结肠癌）中提取的RNA使用nCounter（R）技术与NanoString（R）PanCancer IO 360（TM）CodeSet的β版本杂交。基因表达特征与肿瘤缓解（根据RECIST标准）和总生存期相关。在37例非小细胞肺癌（NSCLC）样本中评估了肿瘤细胞上的PD-L1免疫染色，并在其中19例样本中通过全外显子组测序测量了肿瘤突变负荷（TMB）。结果在整个队列（比值比= 2.64，95% CI [1.4; 6.0]，p = 0.008）以及NSCLC人群（比值比= 3.27，95% CI [1.2; 11.6]，p = 0.03）中，TIS评分与抗PD-1治疗的完全或部分缓解显著相关。肿瘤TIS评分较高的患者（上三分位数）显示与肿瘤TIS评分较低的患者相比，（风险比= 0.37，95% CI [0.18，0.76]，p = 0.005）和NSCLC人群（风险比= 0.36，95% CI [0.14，0.90]，p = 0.02）。在后者中，TIS评分与肿瘤细胞上的PD-L1染色（斯皮尔曼系数0.2）和TMB（斯皮尔曼系数-0.2）无关。结论经验证的基因表达检测技术能够准确、独立地预测肿瘤微环境的炎症反应水平，易于临床应用。
Background The 18-gene tumor inflammation signature (TIS) is a clinical research assay that enriches for clinical benefit to immune checkpoint blockade. We evaluated its ability to predict clinical benefit of immunotherapy in cancer patients treated with PD-1 checkpoint inhibitors in routine clinical care. Methods The CERTIM cohort is a prospective cohort which includes patients receiving immune checkpoint inhibitors in Cochin University hospital. RNA extracted from 58 archival formalin fixed paraffin embedded tumor blocks (including 38 lung cancers, 5 melanomas, 10 renal carcinomas, 4 urothelial carcinomas and 1 colon carcinoma) was hybridized to a beta version of the NanoString (R) PanCancer IO360 (TM) CodeSet using nCounter (R) technology. Gene expression signatures were correlated with tumor responses (by RECIST criteria) and overall survival. PD-L1 immunostaining on tumor cells was assessed in 37 non-small cell lung cancer (NSCLC) samples and tumor mutational burden (TMB) measured by whole exome sequencing in 19 of these. Results TIS scores were significantly associated with complete or partial response to anti-PD-1 treatment in the whole cohort (odds ratio = 2.64, 95% CI [1.4; 6.0], p = 0.008), as well as in the NSCLC population (odds ratio = 3.27, 95% CI [1.2; 11.6], p = 0.03). Patients whose tumor had a high TIS score (upper tertile) showed prolonged overall survival compared to patients whose tumor had lower TIS scores, both in the whole cohort (hazard ratio = 0.37, 95% CI [0.18, 0.76], p = 0.005) and in the NSCLC population (hazard ratio = 0.36, 95% CI [0.14, 0.90], p = 0.02). In the latter, the TIS score was independent from either PD-L1 staining on tumor cells (spearman coefficient 0.2) and TMB (spearman coefficient - 0.2). Conclusions These results indicate that validated gene expression assay measuring the level of tumor microenvironment inflammation such as TIS, are accurate and independent predictive biomarkers and can be easily implemented in the clinical practice.