Abstract A145: Study of mechanisms of immune evasion of oncogenic KRAS in NSCLC

Abstract

Cancer immunotherapies such as immune checkpoint blockade have yielded long-term durable responses in some patients. Nevertheless, the majority of cancer patients do not respond to such therapies, which constitutes a large unmet need in the clinic. Tumors develop mechanisms by which they are able to evade the actions of the immune system, some of which may render them unresponsive to drugs aimed to boost antitumor immunity. Lung cancer is a highly immunogenic tumor type in which, if effective, cancer immunotherapies have proven to be superior to other treatment modalities. KRAS is an oncogene mutated in a third of lung cancer patients and has been previously shown to trigger immunosuppressive actions by tumour cells. We aim to study the immunosuppressive effects of KRAS mutations in vitro and in clinically relevant mouse models of lung adenocarcinoma. We have generated a tumor cell autonomous KRAS- dependent gene expression profile using in vitro systems. We have set a particular focus on genes playing a role in tumor immune evasion, whose function we are aiming to elucidate using immunogenic in vivo models. We have developed a derivative of the transplantable KRAS mutant murine Lewis lung adenocarcinoma (LLC) cell line in which KRAS activity can be specifically blocked using a small-molecule inhibitor. We aim to unravel the immune infiltration of such tumors and elucidate the specific role of KRAS in shaping its microenvironment. By combining simplistic in vitro models to unravel mechanisms of action and more complex mouse models to prove their clinical relevance, we aim to increase immune visibility of KRAS-mutated lung tumors to make them more susceptible to immune and other therapies. Citation Format: Edurne Mugarza, Febe van Maldegem, Miriam Llorian Sopena, Miriam Molina Arcas, Julian Downward. Study of mechanisms of immune evasion of oncogenic KRAS in NSCLC [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A145.