HPV-associated oropharynx carcinoma (HPVOPC) tumors have a relatively low mutational burden. Elucidating the relative contributions of other tumor alterations, such as DNA methylation alterations, alternative splicing events (ASE), and copy number variation (CNV), could provide a deeper understanding of carcinogenesis drivers in this disease. We applied network propagation analysis to multiple classes of tumor alterations in a discovery cohort of 46 primary HPVOPC tumors and 25 cancer-unaffected controls and validated our findings with TCGA data. We identified significant overlap between differential gene expression networks and all alteration classes, and this association was highest for methylation and lowest for CNV. Significant overlap was seen for gene clusters of G protein-coupled receptor (GPCR) pathways. HPV16–human protein interaction analysis identified an enriched cluster defined by an immune-mediated GPCR signal, including CXCR3 cytokines CXCL9, CXCL10, and CXCL11. CXCR3 was found to be expressed in primary HPVOPC, and scRNA-seq analysis demonstrated CXCR3 ligands to be highly expressed in M2 macrophages. In vivo models demonstrated decreased tumor growth with antagonism of the CXCR3 receptor in immunodeficient but not immunocompetent mice, suggesting that the CXCR3 axis can drive tumor proliferation in an autocrine fashion, but the effect is tempered by an intact immune system. In conclusion, methylation, ASE, and SNV alterations are highly associated with network gene expression changes in HPVOPC, suggesting that ASE and methylation alterations have an important role in driving the oncogenic phenotype. Network analysis identifies GPCR networks, specifically the CXCR3 chemokine axis, as modulators of tumor–immune interactions that may have proliferative effects on primary tumors as well as a role for immunosurveillance; however, CXCR3 inhibition should be used with caution, as these agents may both inhibit and stimulate tumor growth considering the competing effects of this cytokine axis. Further investigation is needed to explore opportunities for targeted therapy in this setting.
人乳头瘤病毒（HPV）相关口咽癌（HPVOPC）肿瘤的突变负荷相对较低。阐明其他肿瘤改变（如DNA甲基化改变、可变剪接事件（ASE）和拷贝数变异（CNV））的相对贡献，可以更深入地理解该疾病的致癌驱动因素。我们在一个包含46例原发性HPVOPC肿瘤和25例未患癌对照的发现队列中，对多类肿瘤改变进行了网络传播分析，并使用TCGA数据验证了我们的发现。我们发现差异基因表达网络与所有改变类别之间存在显著重叠，其中与甲基化的关联性最高，与CNV的关联性最低。在G蛋白偶联受体（GPCR）通路的基因簇中也观察到了显著的重叠。HPV16-人类蛋白质相互作用分析发现了一个由免疫介导的GPCR信号定义的富集簇，包括CXCR3趋化因子CXCL9、CXCL10和CXCL11。研究发现CXCR3在原发性HPVOPC中表达，单细胞RNA测序分析显示CXCR3配体在M2巨噬细胞中高表达。体内模型表明，在免疫缺陷小鼠而非免疫健全小鼠中，拮抗CXCR3受体可减少肿瘤生长，这表明CXCR3轴可以以自分泌方式驱动肿瘤增殖，但这种效应在完整的免疫系统中会受到抑制。总之，甲基化、ASE和单核苷酸变异（SNV）改变与HPVOPC中的网络基因表达变化高度相关，表明ASE和甲基化改变在驱动致癌表型中具有重要作用。网络分析确定GPCR网络，特别是CXCR3趋化因子轴，是肿瘤-免疫相互作用的调节因子，可能对原发性肿瘤具有增殖效应，并在免疫监视中发挥作用；然而，应谨慎使用CXCR3抑制剂，因为考虑到该细胞因子轴的竞争效应，这些药物可能同时抑制和刺激肿瘤生长。需要进一步研究以探索在此背景下进行靶向治疗的机会。
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