Whole-genome doubling induces chromosomal instability to shape the tumor-immune microenvironment and impair the response to immune checkpoint inhibitors in non-small cell lung cancer
Presenter: Cheolyong Joe, BS Session: Tumor Microenvironment Modulators Time: 4/22/2026 9:00:00 AM → 4/22/2026 12:00:00 PM
Authors
Cheolyong Joe , Jinyong Kim , Hyemin Kim , Junsu Choe , Miran Jang , Eunjoo Oh , Naeun Lee , Subin Kim , Sehhoon Park , Hyun Ae Jung , Jong-Mu Sun , Jin Seok Ahn , Myung-Ju Ahn , Joo Kyung Park , Se-Hoon Lee Department of Medicine, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea, Republic of
Abstract
Introduction: Whole genome doubling (WGD), observed in 30-40% of cancers, drives chromosomal instability (CIN), but its role in modulating the immune landscape in NSCLC remains unclear. We investigated how WGD shapes tumor-intrinsic and -extrinsic features to influence immune checkpoint inhibitors (ICI) response. Methods: We analyzed 520 baseline NSCLC tumor tissues (WES, n=520; WTS, n=500). WGD was defined from WES-derived copy number profiles as >50% of the autosomal genome having a major copy number ≥2. Tumor-infiltrating lymphocytes (TILs) were quantified in a subset (n=304) via AI-powered spatial analysis of whole slide images (WSIs). Statistical comparisons utilized Fisher’s exact and Wilcoxon rank-sum tests. Results: Among 520 tumors, 202 (38.8%) were WGD+ and 318 (61.2%) were WGD-. TP53 mutations were significantly enriched in WGD+ tumors (57.4% vs WGD-: 40.3%, p=1.51×10⁻⁴). While the 17p13.1 (TP53) locus was significantly higher in WGD+ cohort (76.7% vs WGD-:39.9%, p=8.82×10⁻¹⁷). Furthermore, this coupling of TP53 mutation and LOH coupling was particularly prominent in WGD+: 90.3% (93/103 pre-WGD mutants) acquired LOH, vs 64.8% (83/128) in WGD- tumors. WGD+ tumors also exhibited a significantly higher burden of HLA Class I LOH burden (≥2 loci in 16.1% vs 6.3%, p=8.42×10⁻⁴). WGD+ tumors also showed significantly lower T cell infiltration. Using ploidy-corrected T cell fractions (n=520), the median T cell fraction was significantly lower in the WGD+ group than in the WGD- group (0.138 vs 0.184, p=4.28×10⁻⁴). Gene set enrichment analysis (GSEA) showed WGD+ tumors enriched metabolic/proliferative programs. In contrast, WGD- tumors upregulated immune-activation pathways. This “immune-cold” profile in WGD+ tumors was confirmed by significantly lower immune scores; median cytolytic activity score was 2.53 vs. 3.08 (p=5.34×10⁻⁵) and median TLS score was 5.40 vs. 6.51 (p=1.05×10⁻¹²). Spatially, AI-powered WSI analysis corroborated this, linking WGD+ tumors to fewer inflamed and more immune-desert phenotypes (p=2.74×10⁻ 3 ). Clinically, WGD status was significantly associated with inferior outcomes. Compared to non-WGD patients, WGD patients demonstrated worse overall survival (HR 1.284, 95% CI 1.050-1.569, p=1.47×10⁻ 2 ) and progression-free survival (HR 1.286, 95% CI 1.057-1.563, p=1.18×10⁻ 2 ). Conclusion: In NSCLC, WGD promotes high genomic instability through TP53 mutation and critical HLA Class I LOH, enabling immune escape. This genomic landscape shapes an immunosuppressive ecosystem characterized by metabolic reprogramming, lower T cell infiltration, and immune-desert phenotypes. As a result, WGD defines an immune-refractory microenvironment and serves as a robust predictive biomarker for unfavorable ICI response.
Disclosure
C. Joe, None.. J. Kim, None.. H. Kim, None.. J. Choe, None.. M. Jang, None.. E. Oh, None.. N. Lee, None.. S. Kim, None.. S. Park, None.. H. Jung, None.. J. Sun, None.. J. Ahn, None.. M. Ahn, None.. J. Park, None.. S. Lee, None.
Cited in
Control: 5704 · Presentation Id: 9628 · Meeting 21436