摘要标题：转移性非小细胞肺癌中PD-L1表达和TMB状态及其对EGFR-TKI治疗或铂类化疗后预后的影响

Background: Programmed cell death 1 ligand (PD-L1) expression and the tumour mutation burden (TMB) are distinct biomarkers of response to anti-PD-1/PD-L1 therapies. The proportion of PD-L1-positive, high-TMB patients and their overlap in newly diagnosed metastatic non-small cell lung cancer (NSCLC) and their effect on prognosis after receiving epidermal growth factor receptor (EGFR)-TKIs or platinum-based chemotherapy were evaluated. 

研究目的：研究表明程序性细胞死亡配体1（PD-L1）表达和肿瘤突变负荷（TMB）均能预测肿瘤患者抗PD-1 / PD-L1疗法的疗效。本研究旨在观察新诊断的转移性非小细胞肺癌（NSCLC）中PD-L1阳性患者和高TMB患者的比例及其是否有重叠，并且评估PD-L1表达和TMB状态对患者接受EGFR-TKI治疗或铂类化疗后预后的影响。

Methods: One hundred eighty-seven NSCLC patients were included. Tumour tissue samples were collected to detect PD-L1 expression and TMB status by immunohistochemistry (using the SP142 antibody) and targeting next-generation sequencing of specific genes, respectively. Correlations between PD-L1 or TMB with clinicopathological characteristics were analysed. 

研究方法：本研究共纳入了187例新诊断的NSCLC患者，包括136例肺腺癌和51例肺鳞癌，这些患者后续根据EFGR基因型检测结果接受了EGFR-TKI治疗或铂类药物为基础的化疗。所有患者在治疗前均留取了肿瘤组织。使用SP142抗体，通过免疫组织化学法检测了肿瘤组织中PD-L1的表达。使用针对特定基因的高通量测序法检测了肿瘤组织的TMB状态。分析了PD-L1表达或TMB状态与患者临床病理特征及预后的相关性。

Results: The PD-L1-positive rates of tumour cells were 37% (≥1%) and 20% (≥50%) in adenocarcinoma (ADC); 55% (≥1%) and 27% (≥50%) in squamous cell carcinoma (SQCC). PD-L1 in tumour cells was significantly associated with the SQCC subtype (P=0.030), male sex in ADC (P<0.001), wild-type ADC (P=0.049) and survival outcome of ADC (P<0.0001). The proportion of high TMB (≥13.7 mutations/Mb) in SQCC was higher than that of ADC (P=0.024). The TMB level did not correlate with survival. There were overlaps between high TMB and PD-L1 expression in patients of SQCC, wild-type ADC and EGFR-mutant ADC (22% vs. 10% vs. 3%, respectively), but the positive degree of PD-L1 did not correlate with TMB. The ADC PD-L1-negative plus low/moderate-TMB group had the longest survival time compared with those that were PD-L1 positive with low/moderate TMB or those that were PD-L1 positive with high TMB (41 mon vs. 8 mon vs. 7 mon, respectively; P<0.0001); this pattern was similar to that observed in wild-type ADC patients (32 mon vs. 6 mon vs. 8.5 mon, respectively; P=0.0005). 

研究结果：以≥1％和≥50％两个阳性程度来统计，结果显示肺腺癌肿瘤细胞的PD-L1阳性率为37％（≥1％）和20％（≥50％）；而肺鳞癌的是55％（≥1％）和27％（≥50％）。结合临床病理特征分析发现，肺鳞癌（P= 0.030）、男性肺腺癌（P<0.001）、EGFR基因野生型肺腺癌（P=0.049）和生存较差肺腺癌（P<0.0001）的肿瘤细胞高表达PD-L1的比例较其他患者高。分析TMB状态发现，肺鳞癌中高TMB（≥13.7个突变/ Mb）患者的比例高于肺腺癌（P=0.024）。不论肺腺癌还是肺鳞癌，TMB水平与生存无关。在肺鳞癌、EGFR野生型肺腺癌和EGFR突变型肺腺癌中，高TMB患者和PD-L1表达患者之间存在重叠，比例分别为22％、10％和3％，但PD-L1的阳性程度与TMB值的高低不相关。综合PD-L1表达和TMB状态的生存分析发现，与PD-L1阳性同时TMB低/中等的NSCLC患者或PD-L1阳性同时TMB高的患者相比，PD-L1阴性同时TMB低/中等组患者的生存时间最长（8个月vs. 7个月vs. 41个月，P<0.0001）；在野生型肺腺癌患者中可以观察到类似的模式（6个月vs. 8.5个月vs. 32个月，P=0.0005）。

Conclusions: There were overlaps between the high-TMB and PD-L1-positive population, but the positive degree of PD-L1 did not correlate with the TMB value. PD-L1 expression was an independent predictor of poor prognosis in ADC patients, but the effect of TMB level on prognosis was small.

研究结论：在新诊断的转移性NSCLC中，高TMB患者和PD-L1表达阳性患者之间存在重叠，但PD-L1的阳性程度与TMB值无相关性。PD-L1表达阳性是肺腺癌患者预后不良的独立预测因子，而TMB水平对预后的影响较小。