Sideras Kostandinos, Biermann Katharina, Yap Kevin, Mancham Shanta, Boor Patrick P C, Hansen Bettina E, Stoop Hans J A, Peppelenbosch Maikel P, van Eijck Casper H, Sleijfer Stefan, Kwekkeboom Jaap, Bruno Marco J
Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
Department of Pathology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
Int J Cancer. 2017 Aug 1;141(3):572-582. doi: 10.1002/ijc.30760. Epub 2017 May 19.
Understanding the mechanisms of immune resistance in pancreatic and ampullary cancers is crucial for the development of suitable biomarkers and effective immunotherapeutics. Our aim was to examine the expression of the immune inhibiting molecules PD-L1, Galectin-9, HVEM, IDO and HLA-G, as well as CD8+ and FoxP3+ tumor infiltrating lymphocytes (TIL), in pancreatic and ampullary cancers, and to relate their individual, as well as their combined expression, to cancer survival. Tumor tissue from 224 patients with resected pancreatic (n = 148) and ampullary (n = 76) cancer was used to construct tissue-microarrays. Expression of immune inhibitory molecules and TIL was examined by immunohistochemistry. We show that immune inhibitory molecules are prevalently expressed. Moreover, high tumor expression of PD-L1 (p = 0.002), Gal-9 (p = 0.003), HVEM (p = 0.001), IDO (p = 0.049), HLA-G (p = 0.004) and high CD8/FoxP3 TIL ratio (p = 0.006) were associated with improved cancer-specific survival. All immune biomarkers, with the exception of IDO, were individually predictive of cancer-specific survival when adjusted for clinicopathologic characteristics. For every additional immune biomarker present survival was almost two-fold prolonged (HR 0.57 95%CI 0.47-0.69, p < 0.0001). When patients with pancreatic and ampullary cancer were analyzed separately the results were similar. We conclude that pancreas and ampullary cancers are rich in expression of immune-inhibitory molecules. These molecules can be targets for future immunotherapeutics, as well as form powerful immunological biomarkers. We propose that such immune biomarker panels be included in future prospective immunotherapy trials.
了解胰腺癌和壶腹癌的免疫抵抗机制对于开发合适的生物标志物和有效的免疫疗法至关重要。我们的目的是检测免疫抑制分子PD-L1、半乳糖凝集素-9、疱疹病毒进入介质（HVEM）、吲哚胺2,3-双加氧酶（IDO）和人类白细胞抗原G（HLA-G），以及CD8+和FoxP3+肿瘤浸润淋巴细胞（TIL）在胰腺癌和壶腹癌中的表达，并将它们的单独表达以及联合表达与癌症生存率相关联。来自224例接受手术切除的胰腺癌（n = 148）和壶腹癌（n = 76）患者的肿瘤组织用于构建组织微阵列。通过免疫组织化学检测免疫抑制分子和TIL的表达。我们发现免疫抑制分子普遍表达。此外，PD-L1（p = 0.002）、半乳糖凝集素-9（Gal-9，p = 0.003）、HVEM（p = 0.001）、IDO（p = 0.049）、HLA-G（p = 0.004）的高肿瘤表达以及高CD8/FoxP3 TIL比值（p = 0.006）与癌症特异性生存率的提高相关。在根据临床病理特征进行调整后，除IDO外，所有免疫生物标志物均可单独预测癌症特异性生存率。每增加一种免疫生物标志物，生存率几乎延长两倍（风险比0.57，95%置信区间0.47 - 0.69，p < 0.0001）。当分别分析胰腺癌和壶腹癌患者时，结果相似。我们得出结论，胰腺癌和壶腹癌富含免疫抑制分子的表达。这些分子可成为未来免疫疗法的靶点，也可形成强大的免疫生物标志物。我们建议在未来的前瞻性免疫治疗试验中纳入此类免疫生物标志物组合。
