878P - INHBA is overexpressed in HPV-negative oropharyngeal squamous cell carcinoma and contributes to an aggressive phenotype

Background

There has been considerable progress in comprehending the molecular mechanisms involved in oropharyngeal squamous cell carcinoma (OPSCC). However, the fundamental factors contributing to the aggressiveness of HPV-negative OPSCC compared to the more indolent HPV-positive OPSCC remain unclear. Additionally, the therapeutic options available for this particular cancer subtype are limited. This study aimed to identify potential therapeutic targets for HPV-negative OPSCC by investigating the distinct molecular pathways differentiating HPV-negative from HPV-positive OPSCC.

Methods

Bulk mRNA sequencing of 23 HPV-negative and 39 HPV-positive OPSCC tumors (n = 62) was performed. Gene set enrichment analysis identified the top enriched biological processes in HPV-negative compared to HPV-positive OPSCC. The most upregulated gene in HPV-negative tumors, inhibin subunit beta A (INHBA) was knocked down in an HPV-negative OPSCC cell line to confirm its impact on proliferation, migration, clonogenic survival and cell death. Correlation analyses were conducted to assess the impact of INHBA on the immunologic tumor microenvironment.

Results

Epithelial-to-mesenchymal transition (EMT) was the most enriched process in HPV-negative OPSCC, with INHBA as the most upregulated gene. Knockdown of INHBA led to a downregulation of EMT transcription factors and reduced migration, proliferation, clonal expansion, and cell death resistance of OPSCC cells. We discovered that INHBA was associated with an immunologic pro-tumor microenvironment, as it negatively correlated with anti-tumor CD8+ T and B cells and positively correlated with pro-tumor M1 macrophages. Three miRNAs were identified as potential regulators of INHBA expression.

Conclusions

In conclusion, the upregulation of INHBA promotes cancer aggressiveness. INHBA may be targeted therapeutically (e.g. using metformin) in INHBA-enriched tumors in HPV-negative OPSCC patients to improve their outcome. Our findings may explain the counter intuitive observations that HNSCC patients receiving metformin for diabetes mellitus display a longer overall survival.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

S. Laban: Other, Personal and Institutional, Speaker, Consultant, Advisor: Merck Sharp and Dohme; Other, Institutional, Speaker, Consultant, Advisor: Bristol Myers Squibb; Other, Institutional, Advisory Board: Sanofi Genzyme. All other authors have declared no conflicts of interest.