Analysis of the whole transcriptome from gingivo-buccal squamous cell carcinoma reveals deregulated immune landscape and suggests targets for immunotherapy

Background
Gingivo-buccal squamous cell carcinoma (GBSCC) is one of the most common oral cavity cancers in India with less than 50% patients surviving past 5 years. Here, we report a whole transcriptome profile on a batch of GBSCC tumours with diverse tobacco usage habits. The study provides an entire landscape of altered expression with an emphasis on searching for targets with therapeutic potential.
Methods
Whole transcriptomes of 12 GBSCC tumours and adjacent normal tissues were sequenced and analysed to explore differential expression of genes. Expression changes were further compared with those in TCGA head and neck cohort (n = 263) data base and validated in an independent set of 10GBSCC samples.
Results
Differentially expressed genes (n = 2176) were used to cluster the patients based on their tobacco habits, resulting in 3 subgroups. Immune response was observed to be significantly aberrant, along with cell adhesion and lipid metabolism processes. Different modes of immune evasion were seen across 12 tumours with up-regulation or consistent expression of CD47, unlike other immune evasion genes such as PDL1, FUT4, CTLA4 and BTLA which were downregulated in a few samples. Variation in infiltrating immune cell signatures across tumours also indicates heterogeneity in immune evasion strategies. A few actionable genes such as ITGA4, TGFB1 and PTGS1/COX1 were over expressed in most samples.
Conclusion
This study found expression deregulation of key immune evasion genes, such as CD47 and PDL1, and reasserts their potential as effective immunotherapeutic targets for GBSCC, which requires further clinical studies. Present findings reiterate the idea of using transcriptome profiling to guide precision therapeutic strategies.

背景
牙龈颊部鳞状细胞癌（Gingivo-buccal squamous cell carcinoma, GBSCC）是印度最常见的口腔癌之一，患者5年生存率不足50%。本研究针对一批存在不同烟草使用习惯的GBSCC肿瘤样本开展全转录组分析，全面描绘了基因表达异常的整体图谱，并重点筛选具备治疗潜力的靶点。

方法
对12例GBSCC肿瘤及配对癌旁正常组织进行全转录组测序与分析，以探究基因的差异表达情况。将所得表达变化数据与癌症基因组图谱（The Cancer Genome Atlas, TCGA）头颈部队列数据库（n=263）进行对比，并在独立的10例GBSCC样本队列中完成验证。

结果
共筛选得到2176个差异表达基因，以此根据患者的烟草暴露习惯进行聚类分析，最终分为3个亚组。研究发现免疫应答、细胞黏附与脂质代谢过程均存在显著异常。12例肿瘤中存在多种免疫逃逸模式：CD47呈现上调或持续表达，而PDL1、FUT4、CTLA4、BTLA等其他免疫逃逸基因在部分样本中呈下调状态。不同肿瘤的浸润免疫细胞特征存在差异，提示免疫逃逸策略存在异质性。ITGA4、TGFB1及PTGS1/COX1等若干可靶向治疗基因在多数样本中呈高表达。

结论
本研究发现CD47、PDL1等关键免疫逃逸基因存在表达失调，再次证实其作为GBSCC有效免疫治疗靶点的潜力，该结论仍需进一步的临床研究验证。本研究结果进一步支持利用转录组分析指导精准治疗策略的理念。