Abstract 3097: Investigating an aggressive molecular subtype of stage I lung adenocarcinoma: Evidences for the acquirement of stem-like and immune evasion phenotype
Authors: Melocchi Valentina , Dama Elisa , Cuttano Roberto , Colangelo Tommaso , Graziano Paolo , Bianchi Fabrizio 
Published: August 2019

Abstract
Lung cancer early diagnosis is effective in reducing the risk of metastatic disease and improve overall survival. However, a significant fraction of patients (~20%) with early stage disease (Stage I) experience tumor recurrence and metastatic disease. Recent advances in high-throughput genomic screening allowed an in-depth molecular profile analyses of lung cancer, with particular emphasis for the identification of prognostic gene expression signatures. Indeed, we recently described the existence of an aggressive lung adenocarcinoma (LUAD) molecular subtype (Stage I), namely C1-LUAD, with a peculiar expression and mutational profile more resembling advanced metastatic cancer. Using an integrative approach relying on computational biology and lung cancer experimental models, we now discovered that this C1-subtype is characterized by stem-like and immune evading phenotype. In particular, gene-set enrichment analysis (GSEA) revealed that ‘C1-LUAD’ tumors are enriched in stem cell (SC) expression signatures (q-value&lt;0.05). Notably, the gene network characterizing the C1-LUAD subtype was downstream to known transcriptional modulators involved in SC biology. In line with this, we found several iPS/Stem and EMT biomarkers overexpressed in C1-LUAD and in a panel of C1-LUAD-like lung cancer cells. Furthermore, forced overexpression of HOXB7 gene, a biomarker of C1-LUAD and a member of the Antp homeobox family, promotes the expansion of lung sphere-forming cells and reprogramming into iPS cells. Lastly, we performed an analysis of the Immune Subtypes and ImmunoPhenoScore in C1-LUAD tumors coupled with tumor mutational burden (TMB) and intra-tumor genetic heterogeneity (ITH) profile, which revealed: i) a predominance of the tumor permissive ‘C1 wound healing' subtype (i.e. high Th2/TAMs, low CD8+Tc); ii) a reduction of the ‘C3 inflammatory' subtype; iii) an increased ITH; and iv) a reduction of neoantigen burden. These are hallmarks of cancer immunoediting process which ultimately favor tumor cell escape. In conclusion, we identified an aggressive subtype of LUAD characterized by a stem-like and immune evasion phenotype. C1-LUAD can be identified by qPCR analysis using a panel of 10 genes, previously validated in a large cohort of FFPE samples. Our findings can contribute to improve survival of lung cancer patients by anticipating diagnosis of aggressive Stage I tumors and may pave the way for developing more effective therapeutic strategies.
Citation Format: Valentina Melocchi, Elisa Dama, Roberto Cuttano, Tommaso Colangelo, Paolo Graziano, Fabrizio Bianchi. Investigating an aggressive molecular subtype of stage I lung adenocarcinoma: Evidences for the acquirement of stem-like and immune evasion phenotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3097.