Genetic and epigenetic landscape of the molecular immuno-signature in HNSCC

Malignant progression exhibits a tightly orchestrated balance between immune effector response and tolerance. However, underlying molecular principles that drive the establishment and maintenance of hot and cold tumor phenotypes remain to be elucidated.

We trained a novel molecular immune classifier based on immune cell subsets related to PD-L1 and IFNG expression, which revealed distinct subgroups of hot and cold tumors in five independent HNSCC cohorts as well as cohorts from other tumor entities. Mutational landscape analyses unraveled a higher CASP8 somatic mutation frequency in hot tumors and characteristic patterns of copy number gains and deletions in cold tumors. In an integrative multi-omics approach we identified EGFR as a key node in a regulatory network related to the cold tumor phenotype. Finally, we established a prognostic gene signature by a progression regression model based on differentially expressed genes between hot and cold tumors for immune checkpoint inhibition (ICI).

In conclusion, our data highlight a complex interplay between genetic and epigenetic events related to molecular immune signatures in HNSCC. These features and the prognostic gene signature could pave the way to improve stratification of cancer patient at higher risk for ICI therapy failure, who might benefit from a combination with EGFR inhibition.

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Publication History

Article published online:
10 June 2020