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
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 nove...
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| Main Authors: | , , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
March 11, 2020
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| In: |
Clinical cancer research
Year: 2020, Volume: 26, Issue: 14, Pages: 3616-3628 |
| ISSN: | 1557-3265 |
| DOI: | 10.1158/1078-0432.CCR-19-3997 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1158/1078-0432.CCR-19-3997 Verlag, lizenzpflichtig, Volltext: https://clincancerres.aacrjournals.org/content/26/14/3616 
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| Author Notes: | Bohai Feng, Ying Shen, Xavier Pastor Hostench, Matthias Bieg, Michaela Plath, Naveed Ishaque, Roland Eils, Kolja Freier, Wilko Weichert, Karim Zaoui, and Jochen Hess |
| Summary: | 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. |
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| Item Description: | Gesehen am 07.09.2020 |
| Physical Description: | Online Resource |
| ISSN: | 1557-3265 |
| DOI: | 10.1158/1078-0432.CCR-19-3997 |