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Immunosignatures associated with TP53 status and co-mutations classify prognostically head and neck cancer patients
Andrea Sacconi1, Paola Muti2,3, Claudio Pulito4
1Clinical Trial Center, Biostatistics and Bioinformatics, IRCCS Regina Elena National Cancer Institute, Rome, 00144, Italy.
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 type composition, in order to define signaling pathways associated with resistance to ICIs. Results were validated on two cohorts of 102 HNSCC patients and 139 HNSCC patients under treatment with PD-L1 inhibitors, respectively, and a cohort of 108 HNSCC HPV negative patients and by in vitro experiments in HNSCC cell lines.
Results:
We observed a significant association between the gene set and TP53 gene status and OS and PFS of 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 three different patient cohorts validation analyses corroborated these findings.
Conclusions:
Immune gene signature sets associated with TP53 status and co-mutations classify with more accuracy HNSCC patients. These biomarkers may be easily implemented in clinical setting.
Insights
TP53 gene mutations and co-mutations impact immune gene expression in head and neck squamous cell carcinoma (HNSCC). These findings identify biomarkers for predicting response to immune checkpoint inhibitors (ICIs) in HNSCC patients.
Area of Science:
- Oncology
- Immunology
- Genomics
Background:
- Immune checkpoint inhibitors (ICIs) offer therapeutic benefits for various cancers, but patient response rates vary.
- Identifying predictive biomarkers for ICI therapy is crucial to maximize patient benefit and address resistance.
Discussion:
- TP53 gene status and co-mutations significantly correlate with overall survival (OS) and progression-free survival (PFS) in head and neck squamous cell carcinoma (HNSCC).
- Tumors with TP53 mutations and co-driver mutations exhibit higher immune gene expression compared to those with TP53 mutations alone.
- Conversely, TP53-mutated MYC signatures are linked to reduced immune gene expression.
Key Insights:
- Immune gene signatures associated with TP53 status and co-mutations accurately classify HNSCC patients.
- These biomarkers demonstrate potential for improved patient stratification in clinical settings.
- Validation across multiple patient cohorts and in vitro experiments confirm these associations.
Outlook:
- Further research can refine these biomarkers for precise patient selection in ICI therapy.
- This approach may lead to novel therapeutic strategies for ICI-resistant HNSCC.
- Clinical implementation of these immune gene signature sets could enhance personalized cancer treatment.
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