Department of Medical Oncology, and.
Robert and Renee Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
JCI Insight. 2018 Feb 22;3(4). doi: 10.1172/jci.insight.98811.
Programmed cell death protein 1 (PD-1) inhibitors have efficacy in treating squamous cell carcinoma of the head and neck (SCCHN), but objective response rates are low. PD-1 ligand (PD-L1) expression alone is not considered a robust predictor of response and additional biomarkers are needed. This 3-year observational cohort followed 126 SCCHN patients treated with anti-PD-1/L1 therapy. Prior to treatment, 81 (64%) had targeted massively parallel tumor sequencing. Of these, 42 (52%) underwent fluorescence-activated cell sorting and PD-L1 immunohistochemistry for tumor immunoprofiling. Six (5%) complete responses (CRs) and 11 (9%) partial responses (PRs) were observed. Those treated with prior chemotherapy (98, 78%) versus only surgery and/or radiation had longer overall survival (OS) (10 vs. 3 months, P = 0.02). Smokers had a higher total mutational burden (TMB) (P = 0.01). Virus-positive patients had a lower TMB (P < 0.01) and improved OS (P = 0.02). Among virus-negative responders, NOTCH1 and SMARCA4 were more frequently mutated and frameshift events in tumor suppressor genes occurred more frequently (P = 0.03). Higher TMB and CD8+ T cell infiltrates predicted anti-PD-1/L1 benefit (P < 0.01, P < 0.01, respectively) among virus-negative tumors. TIM-3/LAG-3 coexpression with PD-1 was higher on T cells among nonresponders (P = 0.03 and 0.02, respectively). Somatic frameshift events in tumor suppressor genes and higher TMB among virus-negative SCCHN tumors predict anti-PD-1/L1 response.
程序性死亡蛋白 1（PD-1）抑制剂在治疗头颈部鳞状细胞癌（SCCHN）方面具有疗效，但客观缓解率较低。PD-1 配体（PD-L1）的表达本身并不能作为反应的有力预测指标，还需要其他生物标志物。这项为期 3 年的观察性队列研究随访了 126 例接受抗 PD-1/L1 治疗的 SCCHN 患者。在治疗前，81 例（64%）患者接受了靶向大规模平行肿瘤测序。其中，42 例（52%）患者进行了荧光激活细胞分选和 PD-L1 免疫组化肿瘤免疫分析。观察到 6 例（5%）完全缓解（CR）和 11 例（9%）部分缓解（PR）。与仅接受手术和/或放疗的患者相比，接受过化疗的患者（98 例，78%）的总生存期（OS）更长（10 个月 vs. 3 个月，P = 0.02）。吸烟者的总突变负担（TMB）更高（P = 0.01）。病毒阳性患者的 TMB 较低（P < 0.01），OS 改善（P = 0.02）。在病毒阴性的应答者中，NOTCH1 和 SMARCA4 更频繁地发生突变，肿瘤抑制基因中的框移事件更频繁发生（P = 0.03）。更高的 TMB 和 CD8+T 细胞浸润预测了病毒阴性肿瘤对 PD-1/L1 的获益（P < 0.01，P < 0.01，分别）。在无应答者中，T 细胞上 PD-1 的 TIM-3/LAG-3 共表达更高（P = 0.03 和 0.02，分别）。病毒阴性 SCCHN 肿瘤中肿瘤抑制基因的体细胞框移事件和更高的 TMB 预测对 PD-1/L1 的反应。
