Cancer Research • 2022-06-01

Viral transcript and tumor immune microenvironment-based transcriptomic profiling of HPV-associated head and neck cancer identifies subtypes associated with prognosis


Daria Kiriy; Dmitry Tychinin; Nikita Kotlov; Olga Kudryashova; Anastasia Nikitina; Andrey Tyshevich; Naira Samarina; Ksenia Demina; Sandrine Degryse; Susan Raju Paul; Mark Poznansky; Krystle Lang Kuhs; James S. Lewis; Robert L. Ferris; Xiaowei Wang; Alexander Bagaev; Nathan Fowler; Lori Wirth; Daniel Faden


Human papillomavirus (HPV)-associated Head and Neck Squamous Cell Carcinoma (HPV+HNSCC) is now the most common HPV-associated malignancy in the United States. Current treatments can be associated with severe side-effects or lack of efficacy yet prognostic biomarkers are limited, slowing efforts to personalize treatment in HPV+HNSCC. Here, we describe the use of a transcriptomic-based analytical platform to analyze expression patterns of viral transcripts, the tumor microenvironment (TME), and viral genome integration, and associate these features with overall survival.

Functional gene expression signatures were analyzed on publicly available HPV+HNSCC expression data (n=266). Unsupervised clustering analysis revealed 5 distinct and novel TME types across patients (immune-enriched non-fibrotic, immune-enriched fibrotic, fibrotic, immune-desert, immune-enriched luminal). These microenvironment subtypes were highly correlated with both overall survival and patient prognosis. Tumors with an immune-enriched microenvironment showed the highest survival rates, whereas fibrotic TME types were associated with poor survival (p < 0.05). Unsupervised clustering of a HPV+HNSCC cohort from The Cancer Genome Atlas (TCGA) (n=53), based on HPV transcript expression, revealed 4 HPV-related subtypes. Each subtype was enriched for distinct viral transcripts: E2/E5, E6/E7, E1/E4 and L1/L2. We then validated TME and HPV transcript-related classifications on an independent HPV+HNSCC cohort (n=132). Utilizing both viral transcript and TME subtypes, we found that the E2/E5 HPV subtype was associated with an immune-enriched TME and had a higher overall survival compared to the other subtypes. The E2/E5 subtype was also enriched for samples without HPV-genome integration, suggesting that HPV episomal DNA status and E2/E5 expression pattern may drive an inflamed microenvironment and improved prognosis. In contrast, E6/E7 subtype samples were associated with the fibrotic and depleted TME types, with lower values of T-cell and B-cell gene expression signatures and a lower survival rate. Both E1/E4 and L1/L2 subtypes were associated with the immune-enriched luminal TME types.

These findings suggest that HPV-transcript expression patterns may drive modulation of the TME, and hence impact prognosis. Further validation of the relationships between viral gene expression, TME, and prognosis is warranted to understand if such subtypes could aid in the development of prognostic biomarkers for treatment selection.
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