Low response rates in immune check-point blockade (ICB)-treated head and neck squamous cell carcinoma (HNSCC) drive a critical need for robust, clinically validated predictive biomarkers. Our group previously showed that stress keratin 17 (CK17) suppresses macrophage-mediated CXCL9/CXCL10 chemokine signaling involved in attracting activated CD8+ T cells into tumors, correlating with decreased response rate to pembrolizumab-based therapy in a pilot cohort of ICB-treated HNSCC (n= 26). Here, we performed an expanded analysis of the predictive value of CK17 in ICB-treated HNSCC according to the REMARK criteria and investigated the gene expression profiles associated with high CK17 expression. Pretreatment samples from pembrolizumab-treated HNSCC patients were stained via immunohistochemistry using a CK17 monoclonal antibody (n= 48) and subjected to spatial transcriptomic profiling (n= 8). Our findings were validated in an independent retrospective cohort (n= 22). CK17 RNA expression in pembrolizumab-treated patients with various cancer types was investigated for predictive significance. Of the 48 patients (60% male, median age of 61.5 years), 21 (44%) were CK17 high, and 27 (56%) were CK17 low. A total of 17 patients (35%, 77% CK17 low) had disease control, while 31 patients (65%, 45% CK17 low) had progressive disease. High CK17 expression was associated with a lack of disease control (p= 0.037), shorter time to treatment failure (p= 0.025), and progression-free survival (PFS,p= 0.004), but not overall survival (OS,p= 0.06). A high CK17 expression was associated with lack of disease control in an independent validation cohort (p= 0.011). PD-L1 expression did not correlate with CK17 expression or clinical outcome. CK17 RNA expression was predictive of PFS and OS in 552 pembrolizumab-treated cancer patients. Our findings indicate that high CK17 expression may predict resistance to ICB in HNSCC patients and beyond.
免疫检查点阻断疗法治疗的头颈部鳞状细胞癌患者应答率较低，亟需建立稳健且经临床验证的预测性生物标志物。本团队前期研究发现，应激角蛋白CK17通过抑制巨噬细胞介导的CXCL9/CXCL10趋化因子信号通路，阻碍活化CD8+ T细胞向肿瘤浸润，在26例接受免疫治疗的HNSCC患者队列中，该现象与帕博利珠单抗治疗应答率降低相关。本研究依据REMARK标准，在扩大样本中系统评估CK17对免疫治疗HNSCC的预测价值，并深入解析高CK17表达相关的基因表达特征。通过对48例帕博利珠单抗治疗的HNSCC患者治疗前样本进行CK17单克隆抗体免疫组化染色，并对其中8例样本进行空间转录组分析，发现：在48例患者（男性占60%，中位年龄61.5岁）中，21例（44%）呈CK17高表达，27例（56%）呈CK17低表达；17例（35%）患者实现疾病控制（其中77%为CK17低表达），31例（65%）出现疾病进展（其中45%为CK17低表达）。高CK17表达与疾病控制缺失显著相关（p=0.037），且与较短的治疗失败时间（p=0.025）和无进展生存期（p=0.004）相关，但与总生存期无显著关联（p=0.06）。在22例独立回顾性验证队列中，高CK17表达同样与疾病控制缺失相关（p=0.011）。PD-L1表达与CK17表达及临床结局均无相关性。对552例接受帕博利珠单抗治疗的泛癌种患者分析显示，CK17 RNA表达可预测无进展生存期和总生存期。本研究证实，高CK17表达可作为HNSCC及其他癌种患者免疫治疗耐药的新型预测标志物。
肿瘤(癌症)患者之家