The immune molecular landscape of the B7 and TNFR immunoregulatory ligand-receptor families in head and neck cancer: A comprehensive overview and the immunotherapeutic implications
The immune molecular landscape of the B7 and TNFR immunoregulatory ligand-receptor families in head and neck cancer: A comprehensive overview and the immunotherapeutic implications
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DOI：
10.1080/2162402x.2017.1288329
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发表时间：
2017-01-01
期刊：
影响因子：
7.2
通讯作者：
Ma, Jun
中科院分区：
文献类型：
--
作者：
Chen, Yu-Pei;Zhang, Jian;Ma, Jun
B7家族和肿瘤坏死因子受体（TNFR）超家族在T细胞共刺激和共抑制通路中起着至关重要的作用，调节T细胞活化、耐受和耗竭;这些通路的治疗调节被转化为有效的新癌症治疗。更好地理解B7和TNFR家族的免疫分子景观将指导头颈部免疫肿瘤学临床研究。我们对10名B7和6名TNFR家族成员在头颈癌中进行了全面的分子分析。超过20%的患者存在B7和TNFR基因改变。B7基因扩增（3-11%）比TNFR基因扩增（0-5%）相对更常见。对496个测序样本的分析显示，所有基因均上调：B7和TNFR mRNA分别在158例（> 30%）和83例（接近15%）中上调。B7-H1（PD-L1）mRNA上调最常见（接近10%）。启动子甲基化分析表明B7和TNFR基因调控的表观遗传基础（特别是B7-H1，其与启动子甲基化相对强相关）。B7-H1的表达与总生存率的降低显著相关，并且在基因扩增的病例中其表达增加。人乳头瘤病毒（HPV）状态与B7-H1基因水平的改变显着相关。几乎一半（47.1%）的HPV阴性患者存在深度或浅度B7-H1缺失; >90%的HPV阳性患者存在二倍体、拷贝数增加或B7-H1扩增。这是第一项阐明B7和TNFR家族在头颈癌中的免疫分子景观的研究，为临床研究提供了潜在的新理论基础。
The B7 family and tumor necrosis factor receptor (TNFR) superfamily play a vital role in the T-cell costimulatory and co-inhibitory pathways, regulating T-cell activation, tolerance, and exhaustion; therapeutic modulation of these pathways is translated into effective new cancer treatments. Better understanding of the immune molecular landscapes of the B7 and TNFR families would guide head and neck immuno-oncology clinical research. We performed comprehensive molecular profiling of 10 B7 and 6 TNFR family members in head and neck cancer. Over 20% of patients had B7 and TNFR gene alterations. B7 gene amplifications were relatively more common (3-11%) than TNFR gene amplifications (0-5%). Analysis of 496 sequenced samples revealed that all genes were upregulated: B7 and TNFR mRNA were upregulated in 158 cases (> 30%) and 83 cases (similar to 15%), respectively. B7-H1 (PD-L1) mRNA upregulation was the most common (similar to 10%). Promoter methylation analysis indicated an epigenetic basis for B7 and TNFR gene regulation (especially B7-H1, which was relatively strongly correlated with promoter methylation). B7-H1 expression was significantly associated with worse overall survival, and its expression was increased in cases with gene amplifications. Human papillomavirus (HPV) status correlated significantly with B7-H1 alterations at genetic level. Almost half (47.1%) of HPV-negative patients had deep or shallow B7-H1 deletion; >90% of HPV-positive patients had diploid, copy number gain, or amplification of B7-H1. This is the first study elucidating the immune molecular landscapes of the B7 and TNFR families in head and neck cancer, providing a potential novel rationale for clinical investigations.