Abstract 1012: Determinants of immune evasion in MET driven lung cancer

Abstract

Abstract PURPOSE: The 5' ectonucleotidase (NT5E) encodes for the CD73 membrane protein that converts the extracellular AMP into adenosine (Ado), an immunosuppressive nucleoside that generates anti-inflammatory responses by stimulating T cell anergy. We aimed to analyze CD73 expression across non-small cell lung cancer (NSCLC) and explore its role in immunomodulation and its predictive value to immunotherapy (ICI). METHODS: We analyzed CD73 (NT5E) expression across lung adenocarcinoma samples from The Cancer Genome Atlas (TCGA) and determined top co-expressed genes or correlations with alterations in lung cancer (LC) driver genes. Correlations were validated in specific cancer cell lines using appropriate treatments to activate or inhibit selected pathways. A CRISPR-Cas9 CD73-knockout cell line model was generated to explore direct regulation of extracellular Ado production, as well as impact on secreted cytokines. Finally, we performed staining of CD73 and other immune-related molecules (CD8+ TILs, PD-L1, STING) in a pilot cohort of NSCLC patients (n=35) treated with first line ICI +/- chemotherapy at the DFCI. RESULTS: TCGA analysis revealed strong correlation between MET and CD73 expression and identified MET altered tumors, either by MET exon 14 skipping mutations (METex14) or MET amplification, as being enriched for high CD73 expression (p=0.03). Functional assays using LC cell lines showed that MET activation increases CD73 expression at a transcriptional and protein level by using qPCR, western-blot and flow-cytometry. Additional adenosinergic-related molecules, including the adenosine receptor A2BR (ADORA2B), were co-regulated in parallel with CD73, defining a specific phenotype. In our pilot cohort of patients, CD73 high expression (2+) was found in 20% of lung tumors, mostly adenocarcinomas, whereas 50% were negative (0+) for CD73 expression. CD73 was positively associated with high CD8+ (p= 0.02). Clinical outcomes are being evaluated to elucidate the potential role of CD73 as a predictive marker to ICI. CONCLUSIONS: MET altered tumors and LC cell lines express high levels of CD73 and other adenosinergic-related molecules, representing a potential mechanism of immune evasion and target for immunotherapy. The potential predictive role of CD73 expression in a larger cohort of patients treated with immune checkpoint inhibition (ICI) will be performed. Citation Format: Maria Saigi, Ryohei Yoshida, Erik H Knelson, Navin R Mahadevan, Amir Vajdi, Israel Cañadas, Tran C Thai, Mark M. Awad, Montse Sánchez-Céspedes, David A Barbie. Determinants of immune evasion in MET driven lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1012.