Immune infiltration in CMdel and CMwt NSCLC by IFNK expression status
CMdel samples with high IFNK expression have increased infiltrate of multiple cell types, including (A) M1 macrophages and (B) CD8 T cells, but decreased (C) neutrophil infiltrate.
Introduction and Hypothesis
Deletions in the 9p21 chromosomal region are common in non-small cell lung cancer (NSCLC) and are associated with worse outcomes following immune checkpoint inhibitor (ICI) therapy. However, it is unclear whether this effect is driven by the loss of the CDKN2A tumor suppressor, collateral loss of the MTAP gene, or the loss of type I interferon genes also located in this region. This study aimed to disentangle these factors by investigating how the combination of 9p21 loss (defined by CDKN2A/MTAP deletion) and low interferon (IFNK) expression impacts the tumor’s molecular landscape, immune environment, and response to ICI treatment.
Methodology
This study analyzed de-identified records from 16,947 NSCLC patients in the Tempus Database who underwent both DNA (Tempus xT) and RNA (Tempus xR) molecular profiling within the Tempus Lens platform. Tumors were classified based on the status of the 9p21 region, with CDKN2A/MTAP deleted (CMdel) samples defined as having biallelic loss of CDKN2A/B and MTAP. Concurrently, tumors were classified as having low IFNK expression (IFNKlo) if their expression level was in the bottom quartile. The study then evaluated the association of this combined biomarker status with genomic alterations, the tumor immune microenvironment, and clinical outcomes in a subset of 1,795 patients treated with first-line ICI-containing therapies.
Impact
The analysis demonstrated that the negative impact of 9p21 loss on ICI response is primarily seen when coupled with low interferon expression. In a cohort of advanced NSCLC patients receiving first-line ICI therapy, patients with both 9p21 loss and low IFNK expression (CMdel/IFNKlo) had the highest rates of progressive disease, trending toward 37%. In contrast, patients with 9p21 loss but high IFNK expression (CMdel/IFNKhi) had disease progression rates (28%) comparable to patients without the deletion (27%-30%). The CMdel/IFNKlo status was also associated with a distinct immune landscape, including a decrease in the estimated proportion of CD8 T cells compared to the IFNK-high group.
These findings suggest that 9p21 deletion alone is an incomplete biomarker for predicting ICI response. Instead, a composite biomarker incorporating both 9p21 copy number status and interferon pathway expression could more accurately stratify patients. This provides a strong rationale for developing therapies aimed at restoring interferon signaling specifically in this patient subgroup. For clinical trial design, this data supports stratifying patients by both 9p21 and interferon status to better evaluate the efficacy of novel immunotherapies or agents designed to overcome an immune-excluded tumor microenvironment.
