Gene expression analysis of TIL rich HPV-driven head and neck tumors reveals a distinct B-cell signature when compared to HPV independent tumors.
Gene expression analysis of TIL rich HPV-driven head and neck tumors reveals a distinct B-cell signature when compared to HPV independent tumors.
复制标题
DOI：
10.18632/oncotarget.10788
复制
发表时间：
2016-08-30
期刊：
影响因子：
--
通讯作者：
SPARC Consortium
中科院分区：
文献类型：
--
作者：
Wood O;Woo J;Seumois G;Savelyeva N;McCann KJ;Singh D;Jones T;Peel L;Breen MS;Ward M;Garrido Martin E;Sanchez-Elsner T;Thomas G;Vijayanand P;Woelk CH;King E;Ottensmeier C;SPARC Consortium
人乳头状瘤病毒（HPV）相关的头颈部鳞状细胞癌（HNSCC）的预后比HPV阴性（HPV（−））对应者更好。这可能是由于HPV阳性（HPV（+））肿瘤中肿瘤浸润淋巴细胞（TIL）数量较多。RNA测序（RNA-Seq）用于评价临床行为的差异是否仅反映了TIL的数值差异，或者在这两种情况下TIL之间是否存在根本的行为差异。通过免疫组织化学对39例HNSCC肿瘤的TIL密度进行评分。在移除16个TILlow肿瘤后，对23个TILhigh/med肿瘤（HPV（+）n=10和HPV（-）n=13）进行RNA-Seq分析。使用EdgeR，鉴定差异表达基因（DEG）。使用个体RNA-Seq/微阵列表达的功能分析（FAIME）和免疫基因RNA转录物计数分析进行免疫子集分析。总共鉴定了1，634个DEG，在HPV（+）肿瘤中观察到显性免疫特征。在将表达谱标准化以解释B细胞和T细胞数量的差异后，保留了437个显著的DEG。B细胞相关特征区分HPV（+）和HPV（-）肿瘤，包括DEG CD 200、GGA 2、ADAM 28、STAG 3、SPIB、VCAM 1、BCL 2和ICOSLG;两个肿瘤队列的TIL之间相对于T细胞的免疫信号在定性上相似。我们的研究结果在两个独立的队列中使用TCGA数据和来自其他HPV（+）HNSCC患者的肿瘤浸润B细胞进行了验证和确认。B细胞相关信号相对于HPV状态分离肿瘤。我们的数据表明，B细胞在HPV（+）HNSCC适应性免疫应答中的作用需要重新评估。
Human papilloma virus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) has a better prognosis than it's HPV negative (HPV(−)) counterpart. This may be due to the higher numbers of tumor-infiltrating lymphocytes (TILs) in HPV positive (HPV(+)) tumors. RNA-Sequencing (RNA-Seq) was used to evaluate whether the differences in clinical behaviour simply reflect a numerical difference in TILs or whether there is a fundamental behavioural difference between TILs in these two settings. Thirty-nine HNSCC tumors were scored for TIL density by immunohistochemistry. After the removal of 16 TILlow tumors, RNA-Seq analysis was performed on 23 TILhigh/med tumors (HPV(+) n=10 and HPV(−) n=13). Using EdgeR, differentially expressed genes (DEG) were identified. Immune subset analysis was performed using Functional Analysis of Individual RNA-Seq/ Microarray Expression (FAIME) and immune gene RNA transcript count analysis. In total, 1,634 DEGs were identified, with a dominant immune signature observed in HPV(+) tumors. After normalizing the expression profiles to account for differences in B- and T-cell number, 437 significantly DEGs remained. A B-cell associated signature distinguished HPV(+) from HPV(−) tumors, and included the DEGs CD200, GGA2, ADAM28, STAG3, SPIB, VCAM1, BCL2 and ICOSLG; the immune signal relative to T-cells was qualitatively similar between TILs of both tumor cohorts. Our findings were validated and confirmed in two independent cohorts using TCGA data and tumor-infiltrating B-cells from additional HPV(+) HNSCC patients. A B-cell associated signal segregated tumors relative to HPV status. Our data suggests that the role of B-cells in the adaptive immune response to HPV(+) HNSCC requires re-assessment.