Abstract B11: RAS orchestrates the increase of interstitial adenosine in lung adenocarcinoma to promote immune evasion

The RAS pathway is frequently activated in human cancers, including lung adenocarcinoma, leading to poor prognosis and resistance to therapy. Despite huge efforts, it is still not possible to target this pathway directly. In contrast, Immune checkpoint blockade has shown remarkable yet varied efficacy in lung cancer. With the aim of finding a vulnerable point in these aggressive tumors, we ask here whether oncogenic RAS shapes the immune landscape of lung adenocarcinoma. We classified human lung adenocarcinoma (LUAD) samples from the publicly available dataset from TCGA according to their RAS activity using a RAS transcriptional signature. We correlated the fraction of twenty-two types of leucocyte present in the samples with RAS activity using CIBERSORT. We also identified the expression of immune-related genes that were associated with RAS activity. We observed that RAS activity correlated with the recruitment of proinflammatory macrophages and neutrophils. RAS activity also correlated with the expression of several immune checkpoint genes (e.g., CD274 (PD-L1), HAVCR2 (TIM-3)) as well as genes related to adenosine metabolism or function (e.g., NT5E (CD73), SLC29A4 (ENT4)). Interstitial adenosine is known to dampen the antitumoral immune response. We validated that NT5E expression was dependent on the RAS-MAPK pathway in vitro in human lung cancer cell lines and in vivo in the KrasG12D-LSL/wt Trp53fl/fl mouse model of lung adenocarcinoma. RAS-active tumors could evade the immune system by increasing adenosine level in the tumor microenvironment, notably by increasing expression of CD73, the enzyme that converts extracellular AMP to adenosine. Patients with highly aggressive and resistant RAS-driven lung cancers could benefit from targeting adenosine metabolism (anti-CD73) or activity (A2AR inhibitors) in combination with other immunotherapies targeting PD-1/PD-L1 and TIM-3. Citation Format: Sophie de Carne, Philip East, Chris Moore, Julian Downward. RAS orchestrates the increase of interstitial adenosine in lung adenocarcinoma to promote immune evasion [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B11.