与人类乳头瘤病毒相关口咽癌治疗失败相关的肿瘤内在特征和免疫相关特征。
Tumor-intrinsic and immune-related features associated with treatment failure in human papillomavirus-related oropharyngeal cancer.
作者信息
Sannigrahi Malay K, Raghav Lovely, Rich Dominick J, Schrank Travis P, Califano Joseph A, Lukens John N, Sun Lova, Morgan Iain M, Cohen Roger B, Lin Alexander, Liu Xinyi, Brown Eric J, You Jianxin, Mirabello Lisa, Mishra Sambit K, Shimunov David, Brody Robert M, Pearson Alexander T, Gimotty Phyllis A, Diab Ahmed, Jalaly Jalal B, Basu Devraj
机构信息
Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania, Philadelphia, PA, USA.
Department of Otorhinolaryngology-Head and Neck Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
出版信息
J Natl Cancer Inst. 2025 Mar 11. doi: 10.1093/jnci/djaf053.
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
50 HPV+ OPSCCs that later recurred (cases) and 50 non-recurrent 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 anti-tumor 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 three 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.
背景
对某些人乳头瘤病毒相关（HPV+）口咽鳞状细胞癌（OPSCC）复发的生物学机制了解有限，阻碍了治疗的个性化。我们旨在确定区分易复发肿瘤的分子特征。
方法
对50例后来复发的HPV+ OPSCC（病例组）和50例在分期、治疗和吸烟史方面匹配的未复发对照进行RNA测序。通过基因集富集分析比较两组，选择的差异通过免疫组织化学进行验证。使用基因集变异分析对每个肿瘤中区分两组的特征进行评分，并评估评分的复发预测能力。
结果
病例组下调了与抗肿瘤免疫相关的通路（FDR校正p<0.05），肿瘤浸润淋巴细胞较少（p<0.001），包括细胞毒性T细胞（p=0.005）。病例组还上调了与细胞分裂和肿瘤进展其他方面相关的通路。上调和下调的通路分别用于为每个肿瘤定义肿瘤进展评分（TPS）和免疫抑制评分（ISS）。TPS和ISS之间的相关性（r=0.603，p<0.001）可能是由于病例组中观察到的DNA修复通路上调，这可能直接促进其进展，并通过限制胞质DNA诱导的炎症来实现。因此，基于磷酸化RPA32（p=0.006）和γ-H2AX（p=0.005）的染色，病例组的双链断裂较少，并且下调了胞质DNA传感通路。由TPS和ISS得出的综合评分优化了复发预测，并以一种可推广到三个外部队列的方式对生存进行了分层。
结论
我们描述了HPV+ OPSCC中DNA损伤减少与其他肿瘤内在和免疫相关的复发风险因素之间的潜在联系，为检测和靶向这种高风险生物学机制提供了机会。
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