HPV通过上调TSLP影响头颈鳞癌PD-L1靶向治疗后复发机制研究

头颈鳞癌PD-L1单抗疗效与人乳头瘤病毒(HPV)感染密切相关，治疗敏感且停药后易复发患者，HPV检测多为阳性且机制不明。我们发现HPV转染头颈细胞后促进胸腺基质淋巴细胞生成素（TSLP）表达。树突细胞（DCs）为PD-L1通路的重要节点，且复发患者头颈上皮及DCs中升高的TSLP水平与肿瘤细胞IFNγ、PI3K、PD-L1增高水平呈明显正相关。由此提出假说“HPV诱导头颈上皮分泌TSLP，TSLP促进DCs分泌IFNγ并激活PI3K/Akt通路调节肿瘤细胞PD-L1持续高表达，导致PD-L1抗体治疗虽敏感但停药后肿瘤细胞重获免疫逃逸能力并复发。”我们拟应用细胞模型研究头颈鳞癌微环境中HPV诱导TSLP表达机制、TSLP及DCs影响PD-L1表达的免疫细胞网络；利用临床样本及动物模型阐明HPV影响头颈鳞癌PD-L1单抗疗效及复发机制；为PD-L1靶向治疗效果提供预测标记物并有效抑制其复发。

Infection with HPV has been shown to be a new risk factor for Head and neck squamous cell carcinoma (HNSCC). We found a strong correlation between HPV infection and programmed death ligand 1 (PD-L1) protein expression in HNSCC, and HPV positive HNSCC patients often relapse after PD-L1 targeted Immunotherapy. Whether p16 can be presumed to be a surrogate biomarker for HPV infection and PD-L1 targeted Immunotherapy in HNSCC is still unclear. It is thus crucial to explore the individual and combined expression patterns of other markers associated with HPV-induced carcinogenesis to assess the biological and oncogenic activities of HPV in HNSCC. Our results demonstrated that TSLP expression in DCs correlated positively with PD-L1 expression, and there were more TSLP、PD-L1 expression in HPV positive HNSCC patients. Furthermore, DCs is the key factor in PD-1/PD-L1 pathway. Together, we hypothesize that HPV promotes TSLP expression on DCs and PD-L1 expression in HNSCC cells, leading to immune escape of HNSCC. In the present proposed research, we will investigate the effect of TSLP on PD-L1 expression on HNSCC cells, and followed effects of P16 as biomarker. The proposed study will shed light on the role of HPV on HNSCC, as well as it may elucidate the involvement of TSLP and P16 in the tumorigenesis and progression of HNSCC.