Harnessing CDK4/6 inhibition to promote T cell-mediated anti-tumor immunity

点击翻译按钮获取中文摘要

Cancer is the leading cause of death worldwide and its numbers are projected to rise further, resulting in an estimated 12 million deaths in 2030. A significant amount of these cancer-related deaths is attributable to lung cancer. Although targeted therapies for lung adenocarcinomas (approx. 40% of all lung cancers) have been developed (e.g. Erlotinib, Alectinib), aggressive, non-kinase KRAS-driven lung adenocarcinoma remains refractory to targeted treatment strategies until today. Additionally, KRAS mutations are frequently associated with concurrent loss of key tumor suppressor genes, such as TP53 or STK11/LKB1 in this tumor type. Currently, increased response rates of lung cancers are observed when treated with immune checkpoint inhibitors rearousing the patient´s own adaptive anti-tumor immunity. However, only a minority of patients responds yet, and it is highly likely that application of multimodal therapy is required to tackle KRAS-driven lung adenocarcinoma. The overall aim of this study addresses the question whether radiation therapy (RTx) and CDK4/6 inhibitors act synergistically to sensitize Kras-driven lung adenocarcinoma towards immune checkpoint inhibitors (ICIs). Specifically, we aim to define the effects of CDK4/6 inhibition on effector T cells in vitro. Secondly, we will analyse the tumor immune microenvironment upon CDK4/6 inhibition in vivo. Knowledge of altered immune cell populations and functions upon CDK4/6 repression will help us in timing the addition of other anti-cancer compounds. Lastly, we will perform a preclinical study to evaluate whether dual modality therapy (CDK4/6 inhibition + RTx), or triple modality therapy (CDK4/6 inhibition + RTx + immune check point inhibitor) have synergistic anti-tumor efficacy towards Kras-driven lung adenocarcinoma. Ultimately, the findings from this project will help clinicians to design informed patient-tailored clinical studies for rapid translation in the human setting.