Integrative Analysis of Multi-omics Data Identified EGFR and PTGS2 as Key Nodes in a Gene Regulatory Network Related to Immune Phenotypes in Head and Neck Cancer

Abstract

Purpose: Malignant progression exhibits a tightly orchestrated balance between immune effector response and tolerance. However, underlying molecular principles that drive the establishment and maintenance of the tumor immune phenotype remain to be elucidated. Experimental Design: We trained a novel molecular classifier based on immune cell subsets related to programmed death-ligand 1 (PD-L1) and interferon γ (IFNγ) expression, which revealed distinct subgroups with higher (cluster A) or lower (subcluster B3) cytotoxic immune phenotypes. Integrative analysis of multi-omics data was conducted to identify differences in genetic and epigenetic landscapes as well as their impact on differentially expressed genes (DEG) among immune phenotypes. A prognostic gene signature for immune checkpoint inhibition (ICI) was established by a least absolute shrinkage and selection operator (LASSO)-Cox regression model. Results: Mutational landscape analyses unraveled a higher frequency of CASP8 somatic mutations in subcluster A1, while subcluster B3 exhibited a characteristic pattern of copy-number alterations affecting chemokine signaling and immune effector response. The integrative multi-omics approach identified EGFR and PTGS2 as key nodes in a gene regulatory network related to the immune phenotype, and several DEGs related to the immune phenotypes were affected by EGFR inhibition in tumor cell lines. Finally, we established a prognostic gene signature by a LASSO-Cox regression model based on DEGs between nonprogressive disease and progressive disease subgroups for ICI. Conclusions: Our data highlight a complex interplay between genetic and epigenetic events in the establishment of the tumor immune phenotype and provide compelling experimental evidence that a patient with squamous cell carcinoma of the head and neck at higher risk for ICI treatment failure might benefit from a combination with EGFR inhibition.

Head and neck squamous cell carcinoma

“…In general, HNSCC tumours are highly infiltrated by immune cells, although the extent and composition of the immune cell infiltrate varies according to anatomical subsite and aetiological agent (smoking versus HPV) 103,104 . Furthermore, distinct immune phenotypes have been identified for HNSCC tumours, and several molecular signatures, incorporating diverse markers, have been identified as classifiers [105][106][107] . These signatures might prove useful for predicting response to different therapies, particularly checkpoint inhibition.…”

The benefits of smoking cessation on survival in cancer patients by integrative analysis of multi‐omics data

“…Values of segment mean bigger than 0.2 were defined as gain and < À0.2 as loss [18]. Chi-square test was used to compare CNV between current smokers and reformed smokers.…”

Clinical significance and potential mechanisms of miR-223-3p and miR-204-5p in squamous cell carcinoma of head and neck: a study based on TCGA and GEO

“…Since the above-mentioned characteristics, re-analyses of gene expression profiles acquired more valuable and significant references for further research studies [32][33][34][35]. Hitherto, numerous profiles, involving coding and noncoding RNA expression profiles, genome variation profiles, protein profiles, and methylation profiles, have been published and reserved in GEO [24], TCGA [26], or Oncomine (https://www.oncomine.org/) [36], which could be re-analyzed.…”