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. 2025 Jul 1;117(7):1366-1376.
doi: 10.1093/jnci/djaf053.

Tumor-intrinsic and immune-related features associated with treatment failure in human papillomavirus-related oropharyngeal cancer

Malay K Sannigrahi  1 , Lovely Raghav  1 , Dominick J Rich  1 , Travis P Schrank  2 , Joseph A Califano  3 , John N Lukens  4 , Lova Sun  5 , Iain M Morgan  6 , Roger B Cohen  5 , Alexander Lin  4 , Xinyi Liu  7 , Eric J Brown  8 , Jianxin You  1   9 , Lisa Mirabello  10 , Sambit K Mishra  10 , David Shimunov  11 , Robert M Brody  1 , Alexander T Pearson  12 , Phyllis A Gimotty  13 , Ahmed Diab  1   8 , Jalal B Jalaly  14 , Devraj Basu  1
Affiliations

Tumor-intrinsic and immune-related features associated with treatment failure in human papillomavirus-related oropharyngeal cancer

Malay K Sannigrahi et al. J Natl Cancer Inst. .

Abstract

Background: Limited understanding of the biology predisposing certain human papillomavirus-related (HPV+) oropharyngeal squamous cell carcinomas (OPSCCs) to relapse impedes therapeutic personalization. We aimed to identify molecular traits that distinguish recurrence-prone tumors.

Methods: Fifty HPV+ OPSCCs that later recurred (cases) and 50 nonrecurrent controls matched for stage, therapy, and smoking history were RNA-sequenced. Groups were compared by gene set enrichment analysis, and select differences were validated by immunohistochemistry. Features discriminating groups were scored in each tumor using gene set variation analysis, and scores were evaluated for recurrence prediction ability.

Results: Cases downregulated pathways linked to antitumor immunity (FDR-adjusted P < .05) and contained fewer tumor-infiltrating lymphocytes (P < .001), including cytotoxic T-cells (P = .005). Cases also upregulated pathways related to cell division and other aspects of tumor progression. Upregulated and downregulated pathways were respectively used to define a tumor progression score (TPS) and immune suppression score (ISS) for each tumor. Correlation between TPS and ISS (r = .603, P < .001) was potentially explained by observed upregulation of DNA repair pathways in cases, which might enhance their progression directly and by limiting cytosolic DNA-induced inflammation. Accordingly, cases contained fewer double-strand breaks based on staining for phospho-RPA32 (P = .006) and γ-H2AX (P = .005) and downregulated the cytosolic DNA sensing pathway. A combined score derived from TPS and ISS optimized recurrence prediction and stratified survival in a manner generalizable to 3 external cohorts.

Conclusions: We describe a potential link in HPV+ OPSCCs between reduced DNA damage and other tumor-intrinsic and immune-related contributors to recurrence risk, opening opportunities to detect and target this high-risk biology.

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Conflict of interest statement

D.B. reports paid consulting for Outrun Therapeutics. A.T.P. reports personal fees from the Prelude Therapeutics Advisory Board, Elevar Advisory Board, AbbVie consulting, Ayala Advisory Board, ThermoFisher Advisory Board, Break Through Cancer Scientific Advisory Board, Merck research funds, Kura Oncology research funds, and EMD Serono research funds. L.S. reports fees from advisory boards for GenMab, Seagen, Bayer, and Medscape, and clinical trial funding for Blueprint, Seagen, IO Biotech, Erasca, Immunocore, and Abbvie. E.J.B. reports serving as a paid consultant for and holding equity in Aprea Therapeutics. Other authors have no conflict of interest to declare.

References

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