非小细胞肺癌中高肿瘤突变负荷与PD-L1通过PD-L1表达水平阻断增加免疫浸润和改善临床结果的相关性

SCI

10 July 2022

Association of High Tumor Mutation Burden in Non–Small Cell Lung Cancers With Increased Immune Infiltration and Improved Clinical Outcomes of PD-L1 Blockade Across PD-L1 Expression Levels

(IF: JAMA Oncol., 33.006)

• Ricciuti B, Wang X, Alessi JV, Rizvi H, Mahadevan NR, Li YY, Polio A, Lindsay J, Umeton R, Sinha R, Vokes NI, Recondo G, Lamberti G, Lawrence M, Vaz VR, Leonardi GC, Plodkowski AJ, Gupta H, Cherniack AD, Tolstorukov MY, Sharma B, Felt KD, Gainor JF, Ravi A, Getz G, Schalper KA, Henick B, Forde P, Anagnostou V, Jänne PA, Van Allen EM, Nishino M, Sholl LM, Christiani DC, Lin X, Rodig SJ, Hellmann MD, Awad MM. Association of High Tumor Mutation Burden in Non-Small Cell Lung Cancers With Increased Immune Infiltration and Improved Clinical Outcomes of PD-L1 Blockade Across PD-L1 Expression Levels. JAMA Oncol. 2022 Jun 16:e221981. 

• Corresponding Author: Mark M. Awad, Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Ave, Dana 1240, Boston, MA 02215 (mark_awad@dfci. harvard.edu).

IMPORTANCE 重要性

Although tumor mutation burden (TMB) has been explored as a potential biomarker of immunotherapy efficacy in solid tumors, there still is a lack of consensus about the optimal TMB threshold that best discriminates improved outcomes of immune checkpoint inhibitor therapy among patients with non–small cell lung cancer (NSCLC).

尽管肿瘤突变负荷（TMB）已被探索为实体瘤免疫治疗疗效的潜在生物标记物，但仍缺乏关于最佳TMB阈值的共识，该阈值最能区分非小细胞肺癌患者免疫检查点抑制剂治疗的改善结果。

OBJECTIVES 目的

To determine the association between increasing TMB levels and immunotherapy efficacy across clinically relevant programmed death ligand–1 (PD-L1) levels in patients with NSCLC.

确定NSCLC患者临床相关程序性死亡配体-1（PD-L1）水平中TMB水平升高与免疫治疗疗效之间的关系。

DESIGN, SETTING, AND PARTICIPANTS 设计、设置与参与者

This multicenter cohort study included patients with advanced NSCLC treated with immunotherapy who received programmed cell death–1 (PD-1) or PD-L1 inhibition in the Dana-Farber Cancer Institute (DFCI), Memorial Sloan Kettering Cancer Center (MSKCC), and in the Stand Up To Cancer (SU2C)/Mark Foundation data sets. Clinicopathological and genomic data were collected from patients between September 2013 and September 2020. Data analysis was performed from November 2021 to February 2022.

这项多中心队列研究纳入了接受免疫治疗的晚期非小细胞肺癌患者，他们在Dana-Farber癌症研究所（DFCI）、斯隆-凯特林纪念癌症中心（MSKCC）或Stand Up To Cancer（SU2C）/ Mark Foundation集中接受了程序性细胞死亡-1（PD-1）或PD-L1抑制。2013年9月至2020年9月期间收集了患者的临床病理学和基因组数据。数据分析时间为2021年11月至2022年2月。

EXPOSURES 暴露

 Treatment with PD-1/PD-L1 inhibition without chemotherapy.

未经化疗的PD-1/PD-L1抑制治疗。

MAIN OUTCOMES AND MEASURES 主要结果与方法

Association of TMB levels with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS).

TMB 水平与客观缓解率 (ORR)、无进展生存期 (PFS) 和总生存期 (OS) 的关系。

RESULTS 结果

 In the entire cohort of 1552 patients with advanced NSCLC who received PD-1/PD-L1 blockade, the median (range) age was 66 (22-92) years, 830 (53.5%) were women, and 1347 (86.8%) had cancer with nonsquamous histologic profile. A regression tree modeling ORR as a function of TMB identified 2 TMB groupings in the discovery cohort (MSKCC), defined as low TMB (≤19.0 mutations per megabase) and high TMB (>19.0 mutations per megabase), which were associated with increasing improvements in ORR, PFS, and OS in the discovery cohort and in 2 independent cohorts (DFCI and SU2C/Mark Foundation). These TMB levels also were associated with significant improvements in outcomes of immunotherapy in each PD-L1 tumor proportion score subgroup of less than 1%, 1% to 49%, and 50% or higher. The ORR to PD-1/PD-L1 inhibition was as high as 57%in patients with high TMB and PD-L1 expression 50% or higher and as low as 8.7%in patients with low TMB and PD-L1 expression less than 1%. Multiplexed immunofluorescence and transcriptomic profiling revealed that high TMB levels were associated with increased CD8-positive, PD-L1–positive T-cell infiltration, increased PD-L1 expression on tumor and immune cells, and upregulation of innate and adaptive immune response signatures.

在1552例接受PD-1/PD-L1阻断的晚期非小细胞肺癌患者的整个队列中，中位（范围）年龄为66（22-92）岁，830名（53.5%）为女性，1347名（86.8%）为非鳞状组织癌。将ORR建模作为TMB函数的回归树，在发现队列（MSKCC）中确定了2个TMB分组，定义为低TMB（每兆碱基≤19.0个突变）和高TMB（每兆碱基＞19.0个突变），这与发现队列和2个独立队列（DFCI和SU2C/Mark Foundation）中ORR、PFS和OS的改善有关。在每个PD-L1肿瘤比例评分低于1%、1%-49%和50%或更高的亚组中，这些TMB水平也与免疫治疗结果的显著改善相关。在TMB高且PD-L1表达为50%或更高的患者中，对PD-1/PD-L1抑制的ORR高达57%，在TMB低且PD-L1表达小于1%的患者中，低至8.7%。多重免疫荧光和转录组分析显示，高TMB水平与CD8阳性、PD-L1阳性T细胞浸润增加、肿瘤和免疫细胞上PD-L1表达增加以及先天性和适应性免疫反应特征是上调有关。

CONCLUSIONS AND RELEVANCE 结论与意义

 These findings suggest that increasing TMB levels are associated with immune cell infiltration and an inflammatory T-cell–mediated response, resulting in increased sensitivity to PD-1/PD-L1 blockade in NSCLC across PD-L1 expression subgroups.

这些发现表明，TMB水平的升高与免疫细胞浸润和炎性T细胞介导的反应有关，导致PD-L1表达亚组对NSCLC中PD-1/PD-L1阻断的敏感性增加。

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