TP53 mutation-associated immunosignatures impact on anti-PD-L1 treatment response in head and neck cancer patients

Background. Immune checkpoint inhibitors (ICIs) are a therapeutic strategy for various cancers although only a subset of patients respond to the therapy. Identifying patients more prone to respond to ICIs may increase the therapeutic benefit and allow studying new approaches for resistant patients. Methods. We analyzed the TCGA cohort of HNSCC patients in relation to their activation of 26 immune gene expression signatures, as well as their cell typecomposition, in order to define signaling pathways associated with resistance to ICIs. Results were validated on a cohort of 102 HNSCC patients under treatment with PD-L1 inhibitors and by in vitro experiments in HNSCC cell lines. Results. We observed a significant association between the gene set and TP53 gene status and other predictors of the response to ICI in HNSCC patients. Surprisingly, the presence of a TP53 mutation together with another co-driver mutation was associated with significantly higher levels of the immune gene expression, in comparison to tumors in which the TP53 gene was mutated alone. In addition, the higher level of TP53 mutated-dependent MYC signature was associated with lower levels of the immune gene expression signature. In vitro and a patient cohort validation corroborated these findings. Conclusions. Immune gene signature sets may classify with more accuracy HNSCC patients responsive to immunotherapy. These biomarkers may be easily implemented in clinical setting.