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 / Bohai Feng, Ying Shen, Xavier Pastor Hostench, Matthias Bieg, Michaela Plath, Naveed Ishaque, Roland Eils, Kolja Freier, Wilko Weichert, Karim Zaoui, and Jochen Hess

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..

Medienart:	E-Artikel

Erscheinungsjahr:	March 11, 2020 2020
Erschienen:	March 11, 2020

Enthalten in:	Zur Gesamtaufnahme - volume:26
Enthalten in:	Clinical cancer research - 26(2020), 14, Seite 3616-3628

Sprache:	Englisch

Beteiligte Personen:	Feng, Bohai, 1991- [VerfasserIn] Shen, Ying, 1987- [VerfasserIn] Hostench, Xavier Pastor [VerfasserIn] Bieg, Matthias [VerfasserIn] Plath, Michaela, 1988- [VerfasserIn] Ishaque, Naveed [VerfasserIn] Eils, Roland, 1965- [VerfasserIn] Freier, Kolja, 1973- [VerfasserIn] Weichert, Wilko, 1970-2023 [VerfasserIn] Zaoui, Karim, 1977- [VerfasserIn] Heß, Jochen, 1971- [VerfasserIn]

Links:	Volltext [lizenzpflichtig] Volltext [lizenzpflichtig]

Anmerkungen:	Gesehen am 07.09.2020

Umfang:	13

doi:	10.1158/1078-0432.CCR-19-3997

funding:
Förderinstitution / Projekttitel:

PPN (Katalog-ID):	1728967309