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. Citation Format: 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. 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 abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7945.
Joe et al. (2026) studied this question.