Genebody specific epigenomic reprogramming of transcriptome promotes immune evasion in oropharyngeal cancer patients in North-Eastern India.

[BACKGROUND] Squamous cell carcinoma of oropharynx (OPSCC), a head and neck squamous cell carcinoma (HNSCC) subtype, exhibits a remarkably high incidence rate in the North-Eastern regions of India. The development of OPSCC is associated with the exposure to smokeless tobacco with or without consumption of alcohol and smoking tobacco. Despite advanced treatment modalities, OPSCC patients still face a dismal prognosis, necessitating a deeper exploration of the underlying molecular characteristics of the disease. While promoter CpG methylation-driven gene expression alterations in OPSCC have been studied, DNA methylation within gene bodies and its biological significance in this cancer subtype remain largely uncharted. This study represents the first endeavour to investigate gene-body specific DNA methylation-driven transcriptome alterations leading to immune response modulation on a genome-wide scale in OPSCC.

[RESULTS] The genome-wide assay of DNA methylation and RNA-sequencing in paired tumour and adjacent normal tissues, employing high-throughput platforms (Illumina), identified gene-body specific somatic alterations within the DNA methylome that led to transcriptomic changes in OPSCC patients from Meghalaya. Integrative analysis of gene-body specific methylation and transcriptome data unveiled 98 epigenetically repressed and 39 epigenetically overexpressed genes. Major discoveries emerged from this study include deregulation of Tryptophan (Trp) metabolism pathway by the gene-body driven epigenetically modulated (TDO2, KYNU and TPH2) genes along with the conjoint impact of the upregulated IDO1, IDO2. The IFN-γ mediated PD-L1/PD-1, PD-L2/PD-1 interactions and dysregulation of Trp metabolism pathway collectively contributed to the depletion of cytotoxic T cells in OPSCC tissues. Upregulation of multiple chemokines-CCL2, CXCL1, CXCL2 promoting abundant infiltration of mast cell and neutrophils having pro-tumour phenotype in tumour microenvironment were observed.

[CONCLUSIONS] These key alterations within tumour cells might effectively modulate the immune dynamics, leading to immune evasion by oropharyngeal malignant cells. The findings offer deep understanding of OPSCC and suggests novel immunotherapeutic targets, for the treatment of this challenging disease.