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作者：SCI天天读
SCI
3 June 2023
Impact of aneuploidy and chromosome 9p loss on tumor immune microenvironment and immune checkpoint inhibitor efficacy in non-small cell lung cancer
(Journal of Thoracic Oncology, IF: 20.121)
Joao V. Alessi, Xinan Wang, Arielle Elkrief, Biagio Ricciuti, Yvonne Y. Li, Hersh Gupta, Liam F. Spurr, Hira Rizvi, Jia Luo, Federica Pecci, Giuseppe Lamberti, Gonzalo Recondo, Deepti Venkatraman, Alessandro Di Federico, Malini M. Gandhi, Victor R. Vaz, Mizuki Nishino, Lynette M. Sholl, Andrew D. Cherniack, Marc Ladanyi, Adam Price, Allison L. Richards, Mark Donoghue, James Lindsay, Bijaya Sharma, Madison M. Turner, Kathleen L. Pfaff, Kristen D. Felt, Scott J. Rodig, Xihong Lin, Matthew L. Meyerson, Bruce E. Johnson, David C. Christiani, Adam J. Schoenfeld, Mark M. Awad
CORRESPONDENCE TO: mark_awad@dfci.harvard.edu
Background 背景
Although gene-level copy-number alterations have been studied as a potential biomarker of immunotherapy efficacy in non-small cell lung cancer (NSCLC), the impact of aneuploidy burden and chromosomal arm-level events on immune checkpoint inhibitor (ICI) efficacy in NSCLC is uncertain.
虽然基因水平的拷贝数改变已被研究证实为非小细胞肺癌（NSCLC）免疫治疗效果判断的潜在生物标志物，但非整倍体负荷和染色体臂级事件对NSCLC免疫检查点抑制剂（ICI）疗效的影响尚不明确。
Methods 方法
Patients who received PD-(L)1 inhibitor at two academic centers were included. Across all 22 chromosomes analyzed, an arm was considered altered if at least 70% of its territory was either gained or deleted. Among nonsquamous NSCLCs which underwent targeted next-generation sequencing, we retrospectively quantified aneuploidy using the adjusted fraction of chromosomal arm alterations (FAA), defined as the number of altered chromosome arms divided by the number of chromosome arms assessed, adjusted for tumor purity.
纳入了在两个学术中心接受PD-(L)1抑制剂治疗的患者。在所有分析的22条染色体中，如果一条染色体的臂至少70%的区域被获得或删除，那么就认为该染色体发生了改变。在接受靶向下一代测序的非鳞状NSCLC中，我们使用染色体臂改变的调整分数（FAA）对非整倍体进行了回顾性量化，FAA定义为改变的染色体臂的数量除以评估的染色体臂数量，并根据肿瘤纯度进行了调整。
Results 结果
Among 2293 nonsquamous NSCLCs identified, the median FAA (mFAA) increased with more advanced cancer stage and decreased with higher PD-L1 tumor proportion score (TPS) levels (mFAA in TPS <1%: 0.09, TPS 1-49%: 0.08, TPS ≥50%: 0.05, P<0.0001). There was a very weak correlation between FAA and tumor mutational burden when taken as continuous variables (R: 0.07, P=0.0005). A total of 765 advanced nonsquamous NSCLCs with available FAA values were treated with ICIs. With decreasing FAA tertiles, there was a progressive improvement in objective response rate (ORR 15.1% in upper tertile vs 23.2% in middle tertile vs 28.4% in lowest tertile, P=0.001), median progression-free survival (mPFS 2.5 vs 3.3 vs 4.1 months, P<0.0001), and median overall survival (mOS 12.5 vs 13.9 vs 16.4 months, P=0.006), respectively. In the arm-level enrichment analysis, chromosome 9p loss (OR: 0.22, Q=0.0002) and chromosome 1q gain (OR: 0.43, Q=0.002) were significantly enriched in ICI non-1 responders after false discovery rate adjustment. Compared to NSCLCs without chromosome 9p loss (N=452), those with 9p loss (N=154), had a lower ORR (28.1% vs 7.8%, P<0.0001), a shorter mPFS (4.1 vs 2.3 months, P<0.0001), and a shorter mOS (18.0 vs 9.6 months, P<0.0001) to immunotherapy. Additionally, among NSCLCs with high PD-L1 expression (TPS ≥50%), chromosome 9p loss was associated with lower ORR (43% vs 6%, P<0.0001), shorter mPFS (6.4 vs 2.6 months, P=0.0006), and shorter mOS (30.2 vs 14.3 months, P=0.0008) to immunotherapy compared to NSCLCs without 9p loss. In multivariable analysis, adjusting for key variables including FAA, chromosome 9p loss, but not 1q gain, retained a significant impact on ORR (HR: 0.25, P<0.001), mPFS (HR: 1.49, P=0.001), and mOS (HR: 1.47, P=0.003). Multiplexed immunofluorescence and computational deconvolution of RNA sequencing data demonstrated that tumors with either high FAA levels or chromosome 9p loss had significantly fewer tumor-associated cytotoxic immune cells.
在2293个非鳞状NSCLC中，中位FAA（mFAA）随癌症晚期增加而增加，随PD-L1肿瘤比例评分（TPS）水平升高而降低（TPS中mFAA<1%：0.09，TPS 1-49%：0.08，TPS≥50%：0.05，P<0.0001）。当作为连续变量时，FAA与肿瘤突变负担之间的相关性很弱（R:0.07，P=0.005）。共有765例晚期非鳞状非小细胞肺癌患者具有可用的FAA数值用ICIs处理。随着FAA三分位数的降低，客观缓解率（上三分位数ORR 15.1%，中三分位数OR 23.2%，中四分位数OR 28.4%，P=0.001）、中位无进展生存期（mPFS 2.5 vs 3.3 vs 4.1个月，P<0.0001）和中位总生存期（mOS 12.5 vs 13.9 vs 16.4个月，P=0.006）分别逐渐改善。在臂水平富集分析中，在错误发现率调整后，ICI非1患者的9p染色体缺失突变（OR:0.22，Q=0.0002）和1q染色体增加突变（OR:0.43，Q=0.002）患者显著富集。与没有9p染色体缺失的NSCLC（N=452）相比，9p缺失的NSCLCs（N=154）对免疫治疗的ORR较低（28.1%vs 7.8%，P<0.0001），mPFS较短（4.1 vs 2.3个月，P<0.0001），并且mOS更短（18.0 vs 9.6个月，P<0.0001）。此外，在具有高PD-L1表达（TPS≥50%）的NSCLC中，与没有9p缺失的NSCLC相比，染色体9p缺失与免疫治疗后较低的ORR（43%对6%，P＜0.0001）、mPFS较短（6.4对2.6个月，P＝0.0006）和mOS较短（30.2对14.3个月，P＝0.0008）有关。在多变量分析中，调整关键变量，包括FAA、染色体9p丢失而不是1q增加，对ORR（HR:0.25，P<0.001）、mPFS（HR:1.49，P=0.001）、，和mOS（HR:1.47，P=0.003）有显著影响。RNA测序数据的多重免疫荧光和计算去卷积表明，具有高FAA水平或染色体9p缺失的肿瘤具有显著更少的肿瘤相关细胞毒性免疫细胞。
Conclusions 结论
Nonsquamous NSCLCs with high aneuploidy and chromosome 9p loss have a distinct tumor immune microenvironment and less favorable outcomes to ICIs.
非鳞状NSCLC具有高度非整倍性和9p染色体缺失，具有特异的肿瘤免疫微环境，对ICIs的预后较差。
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