Sideras Kostandinos, Biermann Katharina, Verheij Joanne, Takkenberg Bart R, Mancham Shanta, Hansen Bettina E, Schutz Hannah M, de Man Robert A, Sprengers Dave, Buschow Sonja I, Verseput Maddy C M, Boor Patrick P C, Pan Qiuwei, van Gulik Thomas M, Terkivatan Turkan, Ijzermans Jan N M, Beuers Ulrich H W, Sleijfer Stefan, Bruno Marco J, Kwekkeboom Jaap
Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center , Rotterdam, the Netherlands.
Department of Pathology, Erasmus MC-University Medical Center , Rotterdam, the Netherlands.
Oncoimmunology. 2017 Jan 3;6(2):e1273309. doi: 10.1080/2162402X.2016.1273309. eCollection 2017.
Novel systemic treatments for hepatocellular carcinoma (HCC) are strongly needed. Immunotherapy is a promising strategy that can induce specific antitumor immune responses. Understanding the mechanisms of immune resistance by HCC is crucial for development of suitable immunotherapeutics. We used immunohistochemistry on tissue-microarrays to examine the co-expression of the immune inhibiting molecules PD-L1, Galectin-9, HVEM and IDO, as well as tumor CD8 lymphocyte infiltration in HCC, in two independent cohorts of patients. We found that at least some expression in tumor cells was seen in 97% of cases for HVEM, 83% for PD-L1, 79% for Gal-9 and 66% for IDO. In the discovery cohort (n = 94), we found that lack of, or low, tumor expression of PD-L1 ( < 0.001), Galectin-9 ( < 0.001) and HVEM ( < 0.001), and low CD8TIL count ( = 0.016), were associated with poor HCC-specific survival. PD-L1, Galectin-9 and CD8TIL count were predictive of HCC-specific survival independent of baseline clinicopathologic characteristics and the combination of these markers was a powerful predictor of HCC-specific survival (HR 0.29; <0.001). These results were confirmed in the validation cohort (n = 60). We show that low expression levels of PD-L1 and Gal-9 in combination with low CD8TIL count predict extremely poor HCC-specific survival and it requires a change in two of these parameters to significantly improve prognosis. In conclusion, intra-tumoral expression of these immune inhibiting molecules was observed in the majority of HCC patients. Low expression of PD-L1 and Galectin-9 and low CD8TIL count are associated with poor HCC-specific survival. Combining immune biomarkers leads to superior predictors of HCC mortality.
肝细胞癌（HCC）迫切需要新型的全身治疗方法。免疫疗法是一种很有前景的策略，能够诱导特异性抗肿瘤免疫反应。了解HCC的免疫抵抗机制对于开发合适的免疫疗法至关重要。我们在组织微阵列上使用免疫组织化学方法，在两个独立的患者队列中检测免疫抑制分子PD-L1、半乳糖凝集素-9、疱疹病毒进入介质（HVEM）和吲哚胺2,3-双加氧酶（IDO）的共表达情况，以及HCC中肿瘤CD8淋巴细胞浸润情况。我们发现，在97%的病例中观察到肿瘤细胞中至少有一些HVEM表达，83%有PD-L1表达，79%有Gal-9表达，66%有IDO表达。在发现队列（n = 94）中，我们发现PD-L1（<0.001）、半乳糖凝集素-9（<0.001）和HVEM（<0.001）的肿瘤表达缺乏或较低，以及CD8肿瘤浸润淋巴细胞（CD8TIL）计数较低（=0.016），均与HCC特异性生存不良相关。PD-L1、半乳糖凝集素-9和CD8TIL计数可独立于基线临床病理特征预测HCC特异性生存，这些标志物的组合是HCC特异性生存的有力预测指标（风险比0.29；<0.001）。这些结果在验证队列（n = 60）中得到证实。我们表明，PD-L1和Gal-9低表达与低CD8TIL计数相结合预示着HCC特异性生存极差，并且需要改变其中两个参数才能显著改善预后。总之，在大多数HCC患者中观察到这些免疫抑制分子的肿瘤内表达。PD-L1和半乳糖凝集素-9低表达以及低CD8TIL计数与HCC特异性生存不良相关。联合免疫生物标志物可更好地预测HCC死亡率。
