Abstract 3230: the Role of TRF2 on Tumor Progression in Non-Small Cell Lung Cancer: Potential Modulating Effect on Myeloid Cells

Background: TRF2 is a key factor involved in telomere protection and has been found to be upregulated in various human cancers. The recent discovery by which TRF2 inhibits recruitment of NK cells and prevents tumor cells from NK-mediated elimination established new strategies for cancer support. Oncogenic KRAS is found in approximately 30% of lung adenocarcinomas, the major histologic subtype of non-small cell lung cancer (NSCLC). Activating mutations in KRAS gene generates a robust inflammatory response in lung adenocarcinomas, characterized by an abundant infiltration of leukocytes including neutrophils. Thus, the concepts of solid (at the tissue level) and liquid (at the blood level, with the involvement of circulating tumor cells-CTCs) microenvironment, are a key element to be taken into account in understanding the mechanisms of carcinogenesis and tumor progression. This study was undertaken to, 1) define the impact of TRF2 expressed by lung carcinoma cells on myeloid cells (both at tissue and circulating level), and, 2) to analyze whether this effect may vary according to cancer cells KRAS mutational status. Materials and Methods: Normal human bronchial epithelial cells (Beas2B) were stably transfected with different variants of KRAS mutations or wild-type gene. We evaluated TRF2 expression and neutrophil recruitment according to the KRAS mutational status in an in vitro Transwell model. In addition, we investigated the presence of CTCs in patients with metastatic NSCLC, as well as the TRF2 expression on CTCs (by using a cytomorphological assessement), and the circulating myeloid cells populations, neutrophils and myeloid-derived suppressor cells (MDSC), by flow cytometry analysis. Results: The expression of TRF2 was differentially modulated based on the mutational status of KRAS, being decreased in KRAS G12V cells. We found an increased recruitment of human neutrophils upon induction of KRAS G12D expression. In addition, we found a significant correlation between the PMN-MDSC phenotype and TRF2-expressing CTCs in patients with metastatic NSCLC. Conclusion: TRF2 expression in CTCs modulates the phenotypic orientation of MDSC. KRAS mutational status affects the expression of TRF2 and neutrophil recruitment. The complexity of the interactions between these different actors highlights mechanisms requiring an accurate understanding and may represent potential new therapeutic targets. Citation Format: Linda Bouhlel, Marius Ilie, Laurie Signetti, Julien Cherfils-Vicini, Eric Selva, Patrick Brest, Charles Hugo Marquette, Eric Gilson, Paul Hofman. The role of TRF2 on tumor progression in non-small cell lung cancer: potential modulating effect on myeloid cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3230.