Abstract 910: Chromosome 3q amplification in lung squamous cell carcinoma is associated to iron metabolism and immune cell exclusion

Abstract Introduction and purpose: Lung squamous cell carcinoma (LUSC) is an aggressive tumor type accounting for 30% of all lung cancers, with a roughly 30% 5-year survival. The genetic nature of these tumors precludes the use of targeted therapies and the standard immunotherapy, either alone or in combination with chemotherapy, results in response rates below 50% after biomarker selection. Better patient selection for immunotherapy regimens requires a better definition of the molecular and immune landscape of LUSC. The purpose of this study is to comprehensively characterize the molecular, clinical and immune context of LUSC to identify novel biomarkers that can guide treatment decisions and to find novel therapeutic targets. Experimental procedures: A multiparametric study including a targeted DNA and RNA sequencing of genes related to tumor-immune system crosstalk was conducted in a cohort of 98 early-stage LUSC patients. Histopathological features including immune infiltrate and metabolic traits were defined by in the LUSC tissues. Consensus clustering algorithm classified the sample transcriptomes, and all this data was cross-analyzed with clinical, molecular and immune annotations. Results: Computational analysis of immuno-oncology gene expression data from 98 LUSC tumors led to the classification in 4 patient subgroups with specific molecular and immune characteristics. Interestingly, we found a genomic amplification of the chromosome region 3q, present in almost 30% of the patients, strongly associated with the low immunogenic, as previously shown, and high tumorigenic subgroup. To know the mechanism behind this robust association and given the nature of relevant genes in this region, we analyzed iron accumulation in the tumor samples. We found that iron-positive tumors showed a reduced infiltration of CD8+ T cells compared to iron-negative tumours. The same tendency was observed in CD4, CD20 and CD68 analyses, further supporting an association of this amplification and iron accumulation with a low immunogenic tumor profile. These results were validated in an independent cohort of early-stage LUSC. Conclusions: Taken together, our results support the possible connection between iron accumulation and 3q amplification as a mechanism for immune exclusion in LUSC. We believe that this molecular alteration can be clinically relevant as a biomarker for immunotherapy selection in LUSC, at least in a neoadjuvant setting. Whether this association applies to other squamous carcinomas or might represent novel therapeutic vulnerabilities ensures further research Citation Format: María Gutiérrez Pérez, Javier Ramos Paradas, David Gómez Sánchez, Ricardo García Luján, Jon Zugazagoitia, Nuria Carrizo, Roxolyana Khoroz, Inés Díaz Cano, Laura García Redondo, Ana B Enguitta, Esther Conde, Eva M Garrido Martín, Álvaro C. Ucero Herrería, Luis Paz-Ares. Chromosome 3q amplification in lung squamous cell carcinoma is associated to iron metabolism and immune cell exclusion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 910.