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

Abstract

BackgroundGingivo-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.MethodsWhole 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.ResultsDifferentially 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.ConclusionThis 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.

Immune Checkpoint Inhibitors in Oral Cavity Squamous Cell Carcinoma and Oral Potentially Malignant Disorders: A Systematic Review

“…The most common methodology for assessing expression of immune checkpoint biomarkers was immunohistochemistry (IHC) in 38 studies [10,, followed by flow cytometry (FC) and polymerase chain reaction (PCR) with 10 [52-61] and 8 [62][63][64][65][66][67][68][69] studies, respectively. A combination of both IHC and PCR were used in seven studies [70][71][72][73][74][75][76], both IHC and FC in four [11,[77][78][79], and one study used a combination of IHC, PCR and FC [80].…”

“…PD-L1 was the most studied biomarker, analyzed in 53 studies [10,11,[15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][34][35][36][37][39][40][41][42][43][44][45][46]48,50,54,[59][60][61]64,65,67,68,[70][71][72][74][75][76][77][78]80,81,86]...…”

“…The most common methodology for assessing expression of immune checkpoint biomarkers was immunohistochemistry (IHC) in 38 studies [ 10 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 ], followed by flow cytometry (FC) and polymerase chain reaction (PCR) with 10 [ 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 ] and 8 [ 62 , 63 , 64 , 65 , 66 , 67 , 68 ,…”

Genes and pathways monotonically dysregulated during progression from normal through leukoplakia to gingivo-buccal oral cancer

“…To complement the clinico-pathological findings, we have identified the landscape of genomic and epigenomic alterations in OSCC-GB patients 8 , 9 . Although some studies based on transcriptomic profiling of patients with head and neck cancer (HNSCC) or OSCC have been published 10 – 12 , these did not pertain to the GB form of OSCC that is highly prevalent in the Indian subcontinent, except for one in 12 patients 13 . Earlier, we had discovered 8 that the landscape of genomic alterations in OSCC-GB is different from that of HNSCC or OSCC.…”

Epigenomic dysregulation-mediated alterations of key biological pathways and tumor immune evasion are hallmarks of gingivo-buccal oral cancer

“…We have previously identified a set of driver genes for OSCC-GB, with significantly enhanced burden of somatic mutations and copy number alterations, some of which are unique compared to drivers of other subtypes of head and neck cancers [9, 10]. Unique findings in OSCC-GB have also been reported by transcriptome-wide studies [11, 12]. OSCC-GB, therefore, deserves to be investigated separately.…”