The following is a summary of “Impact of Aneuploidy and Chromosome 9p Loss on Tumor Immune Microenvironment and Immune Checkpoint Inhibitor Efficacy in NSCLC,” published in the November 2023 issue of Pulmonology by Alessi, et al.

Gene-level copy number alterations may indicate NSCLC immunotherapy efficacy. How aneuploidy burden and chromosomal arm-level events affect immune checkpoint inhibitor (ICI) efficacy in NSCLC was unclear. PD-L1 inhibitor recipients at two research institutes were examined in the study. An arm was modified if at least 70% of its area was added or removed for each of the 22 chromosomes examined. The Researchers measured aneuploidy in nonsquamous NSCLCs that underwent targeted next-generation sequencing using the adjusted percentage of chromosomal arm alterations (FAA). The FAA is the number of altered chromosomal arms divided by the number measured, considering tumor purity. In 2,293 nonsquamous NSCLCs, median FAA increased with cancer severity and decreased with PD-L1 tumor percentage score (TPS) (median FAA in TPS < 1%: 0.09, TPS 1%–49%: 0.08, TPS ≥ 50%: 0.05, P< 0.0001). As a continuous variable, FAA had a modest correlation with tumor mutations (R: 0.07, P= 0.0005). 

There were 765 advanced nonsquamous NSCLCs with FAA values treated with ICIs. As FAA tiers decreased, ORR increased. It was 15.1% higher, 23.2% in the middle, and 28.4% in the lowest tertile (P= 0.001). The median progression-free survival (mPFS) increased from 2.5 to 4.1 months (P< 0.0001), while the median overall survival (mOS) increased from 12.5 to 13.9 months (P= 0.006). After accounting for the false discovery rate, ICI nonresponders had higher rates of chromosomal 9p loss (OR = 0.22, Q = 0.0002) and 1q gain (OR = 0.43, Q = 0.002). Compared to immunotherapy, NSCLCs with 9p loss had poorer ORR (28.1% vs. 7.8%, P< 0.0001), shorter mPFS (4.1 mo vs. 2.3 mo, P< 0.0001), and shorter mOS (18.0 mo vs. 9.6 mo, P< 0.0001). There were 452 NSCLCs without 9p loss and 154 with. NSCLCs with strong PD-L1 expression (TPS ≥ 50%) exhibited worse immunotherapy response rates (43% vs. 6%, P< 0.0001), shorter mPFS (6.4 vs. 2.6 mo, P= 0.0006), and shorter mOS (30.2 vs. 14.3 mo, P= 0.0008) than those without 9p loss. 

After controlling for FAA and other covariates, chromosome 9p loss significantly impacted ORR (HR = 0.25, P< 0.001), mPFS (HR = 1.49, P= 0.001), and mOS (HR = 1.47, P= 0.003). Chromosome 1q gain did not. High FAA levels or chromosome 9p loss caused tumors to have less deadly immune cells, according to multiplexed immunofluorescence and computational deconvolution of RNA sequencing data. Nonsquamous NSCLCs with several aneuploidies and chromosome 9p loss have a distinct immunological milieu and react poorly to ICIs.

Source: sciencedirect.com/science/article/abs/pii/S1556086423005786